Beta blocker

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Beta_blocker

Beta blockers
Drug class
Skeletal formula of propranolol, the first clinically successful beta blocker.
Class identifiers
Synonyms	beta-blockers, β-blockers, beta-adrenergic blocking agents, beta antagonists, beta-adrenergic antagonists, beta-adrenoreceptor antagonists, beta adrenergic receptor antagonists, BB
Use	Hypertension, arrhythmia, etc.
ATC code	C07
Biological target	beta receptors
Clinical data
Drugs.com	Drug Classes
Consumer Reports	Best Buy Drugs
WebMD	MedicineNet  RxList
External links
MeSH	D000319
Legal status

Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage abnormal heart rhythms (arrhythmia), and to protect the heart from a second heart attack after a first heart attack (secondary prevention). They are also widely used to treat high blood pressure, although they are no longer the first choice for initial treatment of most patients.

Beta blockers are competitive antagonists that block the receptor sites for the endogenous catecholamines epinephrine (adrenaline) and norepinephrine (noradrenaline) on adrenergic beta receptors, of the sympathetic nervous system, which mediates the fight-or-flight response. Some block activation of all types of β-adrenergic receptors and others are selective for one of the three known types of beta receptors, designated β₁, β₂ and β₃ receptors. β₁-adrenergic receptors are located mainly in the heart and in the kidneys. β₂-adrenergic receptors are located mainly in the lungs, gastrointestinal tract, liver, uterus, vascular smooth muscle, and skeletal muscle. β₃-adrenergic receptors are located in fat cells.

Beta receptors are found on cells of the heart muscles, smooth muscles, airways, arteries, kidneys, and other tissues that are part of the sympathetic nervous system and lead to stress responses, especially when they are stimulated by epinephrine (adrenaline). Beta blockers interfere with the binding to the receptor of epinephrine and other stress hormones and weaken the effects of stress hormones.

In 1964, James Black synthesized the first clinically significant beta blockers—propranolol and pronethalol; it revolutionized the medical management of angina pectoris and is considered by many to be one of the most important contributions to clinical medicine and pharmacology of the 20th century.

For the treatment of primary hypertension, meta-analyses of studies which mostly used atenolol have shown that although beta blockers are more effective than placebo in preventing stroke and total cardiovascular events, they are not as effective as diuretics, medications inhibiting the renin–angiotensin system (e.g., ACE inhibitors), or calcium channel blockers.

Medical uses

Beta blockers are utilized in the treatment of various conditions related to the heart and vascular system, as well as several other medical conditions. Common heart-related conditions for which beta blockers are well-established include angina pectoris, acute coronary syndromes, hypertension, and arrhythmias such as atrial fibrillation and heart failure. They are also used in the management of other heart diseases, such as hypertrophic obstructive cardiomyopathy, mitral valve stenosis or prolapse, and dissecting aneurysm. Additionally, beta blockers find applications in vascular surgery, the treatment of anxiety states, cases of thyrotoxicosis, glaucoma, migraines, and esophageal varices.

Congestive heart failure

Although beta blockers were once contraindicated in congestive heart failure, as they have the potential to worsen the condition due to their effect of decreasing cardiac contractility, studies in the late 1990s showed their efficacy at reducing morbidity and mortality. Bisoprolol, carvedilol, and sustained-release metoprolol are specifically indicated as adjuncts to standard ACE inhibitor and diuretic therapy in congestive heart failure, although at doses typically much lower than those indicated for other conditions. Beta blockers are only indicated in cases of compensated, stable congestive heart failure; in cases of acute decompensated heart failure, beta blockers will cause a further decrease in ejection fraction, worsening the patient's current symptoms.

Beta blockers are known primarily for their reductive effect on heart rate, although this is not the only mechanism of action of importance in congestive heart failure. Beta blockers, in addition to their sympatholytic β₁ activity in the heart, influence the renin–angiotensin system at the kidneys. Beta blockers cause a decrease in renin secretion, which in turn reduces the heart oxygen demand by lowering the extracellular volume and increasing the oxygen-carrying capacity of the blood. Heart failure characteristically involves increased catecholamine activity on the heart, which is responsible for several deleterious effects, including increased oxygen demand, propagation of inflammatory mediators, and abnormal cardiac tissue remodeling, all of which decrease the efficiency of cardiac contraction and contribute to the low ejection fraction. Beta blockers counter this inappropriately high sympathetic activity, eventually leading to an improved ejection fraction, despite an initial reduction in ejection fraction.

Trials have shown beta blockers reduce the absolute risk of death by 4.5% over a 13-month period. In addition to reducing the risk of mortality, the numbers of hospital visits and hospitalizations were also reduced in the trials. A 2020 Cochrane review found minimal evidence to support the use of beta blockers in congestive heart failure in children, however did identify that from the data available, that they may be of benefit.

Therapeutic administration of beta blockers for congestive heart failure ought to begin at very low doses (1⁄8 of target) with a gradual escalation of the dose. The heart of the patient must adjust to decreasing stimulation by catecholamines and find a new equilibrium at a lower adrenergic drive.

Acute myocardial infarction

Beta blockers are indicated for the treatment of acute myocardial infarctions. During a myocardial infarction, systemic stress causes an increase in circulating catecholamines. This results an increase in heart rate and blood pressure, therefore increasing myocardial oxygen demand. Beta blockers competitively inhibit catecholamines acting on the β₁-adrenergic receptors, thus reducing these detrimental effects and resulting in reduced myocardial oxygen consumption and demand.

A 2019 Cochrane review compared beta blockers with placebo or no intervention, it found that beta blockers probably reduced the short-term risk of reinfarction and the long-term risk of all-cause mortality and cardiovascular mortality. The review identified that beta blockers likely had little to no impact on short-term all-cause mortality and cardiovascular mortality.

Hypertension

Beta blockers are widely used for the treatment of hypertension.

A 2014 Cochrane review found that in individuals with mild-to-moderate hypertension, non-selective beta blockers led to a reduction of -10/-7mmHg (systolic/diastolic) without increased rates of adverse events. At higher doses, it was found to increase the rate of adverse effects such as a reduction in heart rate, without a corresponding reduction in blood pressure.

A 2017 Cochrane review on the use of beta blockers in hypertension found a modest reduction in cardiovascular disease but little to no change in mortality It suggested that the effects of beta blockers are inferior to other anti-hypertensive medications.

Anxiety

Officially, beta blockers are not approved for anxiolytic use by the U.S. Food and Drug Administration. However, many controlled trials in the past 25 years indicate beta blockers are effective in anxiety disorders, though the mechanism of action is not known. The physiological symptoms of the fight-or-flight response (pounding heart, cold/clammy hands, increased respiration, sweating, etc.) are significantly reduced, thus enabling anxious individuals to concentrate on the task at hand.

Musicians, public speakers, actors, and professional dancers have been known to use beta blockers to avoid performance anxiety, stage fright, and tremor during both auditions and public performances. The application to stage fright was first recognized in The Lancet in 1976, and by 1987, a survey conducted by the International Conference of Symphony Orchestra Musicians, representing the 51 largest orchestras in the United States, revealed 27% of its musicians had used beta blockers and 70% obtained them from friends, not physicians. Beta blockers are inexpensive, said to be relatively safe, and on one hand, seem to improve musicians' performances on a technical level, while some, such as Barry Green, the author of "The Inner Game of Music" and Don Greene, a former Olympic diving coach who teaches Juilliard students to overcome their stage fright naturally, say the performances may be perceived as "soulless and inauthentic".

Surgery

Low certainty evidence indicates that the use of beta blockers around the time of cardiac surgery may decrease the risk of heart dysrhythmias and atrial fibrillation. Starting them around the time of other types of surgery, however, may worsen outcomes. For non-cardiac surgery, the use of beta blockers to prevent adverse effects may reduce the risk of atrial fibrillation and myocardial infarctions (very low certainty evidence), however, there is moderate certainty evidence that this approach may increase the risk of hypotension. Low-certainty evidence suggests that beta blockers used perioperatively in non-cardiac surgeries may increase the risk of bradycardia.

Other

A 2014 Cochrane review investigated the use of beta blockers in the maintenance of chronic type B thoracic aortic aneurysm in comparison to other anti hypertensive medications. The review found no suitable evidence to support the current guidelines recommending its use.

A 2017 Cochrane review on the use of beta blockers to prevent aortic dissections in people with Marfan syndrome was unable to draw definitive conclusions due to lack of evidence.

Medical uses

Adrenergic antagonists are mostly used for cardiovascular disease. The adrenergic antagonists are widely used for lowering blood pressure and relieving hypertension. These antagonists have a been proven to relieve the pain caused by myocardial infarction, and also the infarction size, which correlates with heart rate.

There are few non-cardiovascular uses for adrenergic antagonists. Alpha-adrenergic antagonists are also used for treatment of ureteric stones, pain and panic disorders, withdrawal, and anesthesia.

Beta blockers are used to treat acute cardiovascular toxicity (e.g. in overdose) caused by sympathomimetics, for instance caused by amphetamine, methamphetamine, cocaine, ephedrine, and other drugs. Combined α₁ and beta blockers like labetalol and carvedilol may be more favorable for such purposes due to the possibility of "unopposed α-stimulation" with selective beta blockers.

Performance-enhancing use

Because they promote lower heart rates and reduce tremors, beta blockers have been used in professional sports where high accuracy is required, including archery, shooting, golf and snooker. Beta blockers are banned in some sports by the International Olympic Committee. In the 2008 Summer Olympics, 50-metre pistol silver medalist and 10-metre air pistol bronze medalist Kim Jong-su tested positive for propranolol and was stripped of his medals.

For similar reasons, beta blockers have also been used by surgeons.

Classical musicians have commonly used beta blockers since the 1970s to reduce stage fright.

Adverse effects

Adverse drug reactions associated with the use of beta blockers include: nausea, diarrhea, bronchospasm, dyspnea, cold extremities, exacerbation of Raynaud's syndrome, bradycardia, hypotension, heart failure, heart block, fatigue, dizziness, alopecia (hair loss), abnormal vision, hallucinations, insomnia, nightmares, sexual dysfunction, erectile dysfunction, alteration of glucose and lipid metabolism. Mixed α₁/β-antagonist therapy is also commonly associated with orthostatic hypotension. Carvedilol therapy is commonly associated with edema. Due to the high penetration across the blood–brain barrier, lipophilic beta blockers, such as propranolol and metoprolol, are more likely than other less lipophilic beta blockers to cause sleep disturbances, such as insomnia, vivid dreams and nightmares.

Adverse effects associated with β₂-adrenergic receptor antagonist activity (bronchospasm, peripheral vasoconstriction, alteration of glucose and lipid metabolism) are less common with β₁-selective (often termed "cardioselective") agents, but receptor selectivity diminishes at higher doses. Beta blockade, especially of the beta-1 receptor at the macula densa, inhibits renin release, thus decreasing the release of aldosterone. This causes hyponatremia and hyperkalemia.

Hypoglycemia can occur with beta blockade because β₂-adrenoceptors normally stimulate glycogen breakdown (glycogenolysis) in the liver and pancreatic release of the hormone glucagon, which work together to increase plasma glucose. Therefore, blocking β₂-adrenoceptors lowers plasma glucose. β₁-blockers have fewer metabolic side effects in diabetic patients; however, the fast heart rate that serves as a warning sign for insulin-induced low blood sugar may be masked, resulting in hypoglycemia unawareness. This is termed beta blocker-induced hypoglycemia unawareness. Therefore, beta blockers are to be used cautiously in diabetics.

A 2007 study revealed diuretics and beta blockers used for hypertension increase a patient's risk of developing diabetes mellitus, while ACE inhibitors and angiotensin II receptor antagonists (angiotensin receptor blockers) actually decrease the risk of diabetes. Clinical guidelines in Great Britain, but not in the United States, call for avoiding diuretics and beta blockers as first-line treatment of hypertension due to the risk of diabetes.

Beta blockers must not be used in the treatment of selective alpha-adrenergic agonist overdose. The blockade of only beta receptors increases blood pressure, reduces coronary blood flow, left ventricular function, and cardiac output and tissue perfusion by means of leaving the alpha-adrenergic system stimulation unopposed. Beta blockers with lipophilic properties and CNS penetration such as metoprolol and labetalol may be useful for treating CNS and cardiovascular toxicity from a methamphetamine overdose. The mixed alpha- and beta blocker labetalol is especially useful for treatment of concomitant tachycardia and hypertension induced by methamphetamine. The phenomenon of "unopposed alpha stimulation" has not been reported with the use of beta blockers for treatment of methamphetamine toxicity. Other appropriate antihypertensive drugs to administer during hypertensive crisis resulting from stimulant overdose are vasodilators such as nitroglycerin, diuretics such as furosemide, and alpha blockers such as phentolamine.

Contraindications and cautions

Absolute contraindications:

• Bradycardia
• Hypotension
• Hypersensitivity to beta blockers
• Cardiogenic shock
• Second or third degree AV block

Relative contraindications, or contraindications specific to certain beta-blockers:

• Long QT syndrome: sotalol is contraindicated
• History of torsades de pointes: sotalol is contraindicated

Cautions:

• Abrupt discontinuations
• Acute bronchospasm
• Acute heart failure
• Asthma: see below
• Bronchitis
• Cerebrovascular disease
• Chronic obstructive pulmonary disease (COPD)
• Emphysema^[53]
• Kidney failure
• Hepatic disease
• Myopathy
• Pheochromocytoma
• Psoriasis
• Reynaud phenomenon
• Stroke
• Vasospastic angina
• Wolff–Parkinson–White syndrome

Asthma

The 2007 National Heart, Lung, and Blood Institute (NHLBI) asthma guidelines recommend against the use of non-selective beta blockers in asthmatics, while allowing for the use of cardio selective beta blockers.

Cardio selective beta blocker (β₁ blockers) can be prescribed at the least possible dose to those with mild to moderate respiratory symptoms. β2-agonists can somewhat mitigate β-blocker-induced bronchospasm where it exerts greater efficacy on reversing selective β-blocker-induced bronchospasm than the nonselective β-blocker-induced worsening asthma and/or COPD.

Diabetes mellitus

Epinephrine signals early warning of the upcoming hypoglycemia.

Beta blockers' inhibition on epinephrine's effect can somewhat exacerbate hypoglycemia by interfering with glycogenolysis and mask signs of hypoglycemia such as tachycardia, palpitations, diaphoresis, and tremors. Diligent blood glucose level monitoring is necessary for a patient with diabetes mellitus on beta blocker.

Hyperthyroidism

Abrupt withdrawal can result in a thyroid storm.

Bradycardia or AV block

Unless a pacemaker is present, beta blockers can severely depress conduction in the AV node, resulting in a reduction of heart rate and cardiac output. One should be very cautious with the use of beta blockers in tachycardia patients with Wolff-Parkinson-White Syndrome, as it can result in life-threatening arrhythmia in certain patients. By slowing the conduction through the AV node, preferential conduction through the accessory pathway is favored. If the patient happens to develop atrial flutter, this could lead to a 1:1 conduction with very fast ventricular rate, or worse, ventricular fibrillation in the case of atrial fibrillation.

Toxicity

Glucagon, used in the treatment of overdose, increases the strength of heart contractions, increases intracellular cAMP, and decreases renal vascular resistance. It is, therefore, useful in patients with beta blocker cardiotoxicity. Cardiac pacing is usually reserved for patients unresponsive to pharmacological therapy.

People experiencing bronchospasm due to the β₂ receptor-blocking effects of nonselective beta blockers may be treated with anticholinergic drugs, such as ipratropium, which are safer than beta agonists in patients with cardiovascular disease. Other antidotes for beta blocker poisoning are salbutamol and isoprenaline.

Pharmacology

Intrinsic sympathomimetic activity

Also referred to as intrinsic sympathomimetic effect, this term is used particularly with beta blockers that can show both agonism and antagonism at a given beta receptor, depending on the concentration of the agent (beta blocker) and the concentration of the antagonized agent (usually an endogenous compound, such as norepinephrine). See partial agonist for a more general description.

Some beta blockers (e.g. oxprenolol, pindolol, penbutolol, labetalol and acebutolol) exhibit intrinsic sympathomimetic activity (ISA). These agents are capable of exerting low-level agonist activity at the β-adrenergic receptor while simultaneously acting as a receptor site antagonist. These agents, therefore, may be useful in individuals exhibiting excessive bradycardia with sustained beta blocker therapy.

Agents with ISA should not be used for patients with any kind of angina as it can aggravate or after myocardial infarctions. They may also be less effective than other beta blockers in the management of angina and tachyarrhythmia.

β-Adrenergic receptor antagonism

Stimulation of β₁ receptors by epinephrine and norepinephrine induces a positive chronotropic and inotropic effect on the heart and increases cardiac conduction velocity and automaticity. Stimulation of β₁ receptors on the kidney causes renin release. Stimulation of β₂ receptors induces smooth muscle relaxation, induces tremor in skeletal muscle, and increases glycogenolysis in the liver and skeletal muscle. Stimulation of β₃ receptors induces lipolysis.

Beta blockers inhibit these normal epinephrine- and norepinephrine-mediated sympathetic actions, but have minimal effect on resting subjects. That is, they reduce the effect of excitement or physical exertion on heart rate and force of contraction, and also tremor, and breakdown of glycogen. Beta blockers can have a constricting effect on the bronchi of the lungs, possibly worsening or causing asthma symptoms.

Since β₂ adrenergic receptors can cause vascular smooth muscle dilation, beta blockers may cause some vasoconstriction. However, this effect tends to be small because the activity of β₂ receptors is overshadowed by the more dominant vasoconstricting α₁ receptors. By far the greatest effect of beta blockers remains in the heart. Newer, third-generation beta blockers can cause vasodilation through blockade of alpha-adrenergic receptors.

Accordingly, nonselective beta blockers are expected to have antihypertensive effects. The primary antihypertensive mechanism of beta blockers is unclear, but may involve reduction in cardiac output (due to negative chronotropic and inotropic effects). It may also be due to reduction in renin release from the kidneys, and a central nervous system effect to reduce sympathetic activity (for those beta blockers that do cross the blood–brain barrier, e.g. propranolol).

Antianginal effects result from negative chronotropic and inotropic effects, which decrease cardiac workload and oxygen demand. Negative chronotropic properties of beta blockers allow the lifesaving property of heart rate control. Beta blockers are readily titrated to optimal rate control in many pathologic states.

The antiarrhythmic effects of beta blockers arise from sympathetic nervous system blockade—resulting in depression of sinus node function and atrioventricular node conduction, and prolonged atrial refractory periods. Sotalol, in particular, has additional antiarrhythmic properties and prolongs action potential duration through potassium channel blockade.

Blockade of the sympathetic nervous system on renin release leads to reduced aldosterone via the renin–angiotensin–aldosterone system, with a resultant decrease in blood pressure due to decreased sodium and water retention.

α₁-Adrenergic receptor antagonism

Some beta blockers (e.g., labetalol and carvedilol) exhibit mixed antagonism of both β- and α₁-adrenergic receptors, which provides additional arteriolar vasodilating action.

Blood–brain barrier permeability

Beta blockers vary in their lipophilicity (fat solubility) and in turn in their ability to cross the blood–brain barrier and exert effects in the central nervous system. Beta blockers with greater blood–brain barrier permeability can have both neuropsychiatric therapeutic benefits and side effects, as well as adverse cognitive effects. Central nervous system-related side effects and risks of beta blockers may include fatigue, depression, sleep disorders (namely insomnia) and nightmares, visual hallucinations, delirium, psychosis, Parkinson's disease, and falling. Conversely, central nervous system-related benefits of beta blockers may include prevention and treatment of migraine, essential tremor, akathisia, anxiety, post-traumatic stress disorder, aggression, and obsessive–compulsive disorder.

Most beta blockers are lipophilic and can cross into the brain, but there are a number of exceptions. Highly lipophilic beta blockers include penbutolol, pindolol, propranolol, and timolol, moderately lipophilic beta blockers include acebutolol, betaxolol, bisoprolol, carvedilol, metoprolol, and nebivolol, and low lipophilicity or hydrophilic beta blockers include atenolol, carteolol, esmolol, labetalol, nadolol, and sotalol. It is thought that highly lipophilic beta blockers are able to readily cross into the brain, moderately lipophilic beta blockers are able to cross to a lesser degree, and low lipophilicity or hydrophilic beta blockers are minimally able to cross. More lipophilic beta-blockers are known to suppress melatonin release by 50-80%. The preceding beta blockers also vary in their intrinsic sympathomimetic activity and β₁-adrenergic receptor selectivity (or cardioselectivity), resulting in further differences in pharmacological profiles and suitability in different contexts between them.

Agents

Dichloroisoprenaline, the first beta blocker

Nonselective agents

Nonselective beta blockers display both β₁ and β₂ antagonism.

• Propranolol
• Bucindolol (has additional α₁-blocking activity)
• Carteolol
• Carvedilol (has additional α₁-blocking activity)
• Labetalol (has intrinsic sympathomimetic activity and additional α₁-blocking activity)
• Nadolol
• Oxprenolol (has intrinsic sympathomimetic activity)
• Penbutolol (has intrinsic sympathomimetic activity)
• Pindolol (has intrinsic sympathomimetic activity)
• Sotalol (not considered a "typical beta blocker")
• Timolol

β₁-selective agents

β₁-selective beta blockers are also known as cardioselective beta blockers. Pharmacologically, the beta-blockade of the β₁ receptors in the heart will act on cAMP. The function of cAMP as a second messenger in the cardiac cell is that it phosphorylates the LTCC and the ryanodine receptor to increase intracellular calcium levels and cause contraction. Beta-blockade of the β₁ receptor will inhibit cAMP from phosphorylating, and it will decrease the ionotrophic and chronotropic effect. Note that drugs may be cardioselective, or act on β₁ receptors in the heart only, but still have instrinsic sympathomimetic activity.

• Acebutolol (has intrinsic sympathomimetic activity, ISA)
• Atenolol
• Betaxolol
• Bisoprolol
• Celiprolol (has intrinsic sympathomimetic activity)
• Metoprolol
• Nebivolol
• Esmolol

Nebivolol and bisoprolol are the most β₁ cardioselective beta blockers.

β₂-selective agents

• Butaxamine
• ICI-118,551

β₃-selective agents

• SR 59230A

β₁ selective antagonist and β₃ agonist agents

• Nebivolol

Comparative information

Pharmacological differences

• Agents with intrinsic sympathomimetic action (ISA)
  • Acebutolol, pindolol, labetalol, mepindolol, oxprenolol, celiprolol, penbutolol
• Agents organized by lipid solubility (lipophilicity)
  • High lipophilicity: propranolol, labetalol
  • Intermediate lipophilicity: metoprolol, bisoprolol, carvedilol, acebutolol, timolol, pindolol
  • Low lipophilicity (also known as hydrophilic beta blockers): atenolol, nadolol, and sotalol
• Agents with membrane stabilizing effect
  • Carvedilol, propranolol > oxprenolol > labetalol, metoprolol, timolol

Indication differences

• Agents specifically labeled for cardiac arrhythmia
  • Esmolol, sotalol, landiolol (Japan)
• Agents specifically labeled for congestive heart failure
  • Bisoprolol, carvedilol, sustained-release metoprolol
• Agents specifically labeled for glaucoma
  • Betaxolol, carteolol, levobunolol, timolol, metipranolol
• Agents specifically labeled for myocardial infarction
  • Atenolol, metoprolol (immediate release), propranolol (immediate release), timolol, carvedilol (after left ventricular dysfunction), bisoprolol (preventive treatment before and primary treatment after heart attacks)
• Agents specifically labeled for migraine prophylaxis
  • Timolol, propranolol

Propranolol is the only agent indicated for the control of tremor, portal hypertension, and esophageal variceal bleeding, and used in conjunction with α-blocker therapy in phaeochromocytoma.

Other effects

Beta blockers, due to their antagonism at beta-1 adrenergic receptors, inhibit both the synthesis of new melatonin and its secretion by the pineal gland. The neuropsychiatric side effects of some beta blockers (e.g. sleep disruption, insomnia) may be due to this effect.

Some pre-clinical and clinical research suggests that some beta blockers may be beneficial for cancer treatment. However, other studies do not show a correlation between cancer survival and beta blocker usage. Also, a 2017 meta-analysis failed to show any benefit for the use of beta blockers in breast cancer.

Beta blockers have also been used for the treatment of schizoid personality disorder. However, there is limited evidence supporting the efficacy of supplemental beta blocker use in addition to antipsychotic drugs for treating schizophrenia.

Contrast agents are not contraindicated in those receiving beta blockers.

Hypothalamus

From Wikipedia, the free encyclopedia

Not to be confused with Subthalamus.

 

Hypothalamus
Location of the human hypothalamus
Location of the hypothalamus (cyan) in relation to the pituitary and to the rest of the brain
Details
Part of	Brain
Identifiers
Latin	hypothalamus
MeSH	D007031
NeuroLex ID	birnlex_734
TA98	A14.1.08.401 A14.1.08.901
TA2	5714
FMA	62008

The hypothalamus (pl.: hypothalami; from Ancient Greek ὑπό (hupó) 'under' and θάλαμος (thálamos) 'chamber') is a small part of the vertebrate brain that contains a number of nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamus is located below the thalamus and is part of the limbic system. It forms the basal part of the diencephalon. All vertebrate brains contain a hypothalamus. In humans, it is about the size of an almond.

The hypothalamus has the function of regulating certain metabolic processes and other activities of the autonomic nervous system. It synthesizes and secretes certain neurohormones, called releasing hormones or hypothalamic hormones, and these in turn stimulate or inhibit the secretion of hormones from the pituitary gland. The hypothalamus controls body temperature, hunger, important aspects of parenting and maternal attachment behaviours, thirst, fatigue, sleep, circadian rhythms, and is important in certain social behaviors, such as sexual and aggressive behaviors.

Structure

The hypothalamus is divided into four regions (preoptic, supraoptic, tuberal, mammillary) in a parasagittal plane, indicating location anterior-posterior; and three zones (periventricular, intermediate, lateral) in the coronal plane, indicating location medial-lateral. Hypothalamic nuclei are located within these specific regions and zones. It is found in all vertebrate nervous systems. In mammals, magnocellular neurosecretory cells in the paraventricular nucleus and the supraoptic nucleus of the hypothalamus produce neurohypophysial hormones, oxytocin and vasopressin. These hormones are released into the blood in the posterior pituitary. Much smaller parvocellular neurosecretory cells, neurons of the paraventricular nucleus, release corticotropin-releasing hormone and other hormones into the hypophyseal portal system, where these hormones diffuse to the anterior pituitary.

Nuclei

The hypothalamic nuclei include the following:

List of nuclei, their functions, and the neurotransmitters, neuropeptides, or hormones that they utilize

Region	Area	Nucleus	Function
Anterior (supraoptic)	Preoptic	Preoptic nucleus	Thermoregulation
		Ventrolateral preoptic nucleus	Sleep
	Medial	Medial preoptic nucleus	Regulates the release of gonadotropic hormones from the adenohypophysis Contains the sexually dimorphic nucleus, which releases GnRH, differential development between sexes is based upon in utero testosterone levels Thermoregulation
		Supraoptic nucleus	Vasopressin release Oxytocin release
		Paraventricular nucleus	thyrotropin-releasing hormone release corticotropin-releasing hormone release oxytocin release vasopressin release somatostatin round arousal (wakefulness and attention) appetite
		Anterior hypothalamic nucleus	thermoregulation panting sweating thyrotropin inhibition
		Suprachiasmatic nucleus	Circadian rhythms
	Lateral	Lateral nucleus	See Lateral hypothalamus § Function – primary source of orexin neurons that project throughout the brain and spinal cord
Middle (tuberal)	Medial	Dorsomedial hypothalamic nucleus	blood pressure heart rate GI stimulation
		Ventromedial nucleus	satiety neuroendocrine control
		Arcuate nucleus	Growth hormone-releasing hormone (GHRH) feeding Dopamine-mediated prolactin inhibition
	Lateral	Lateral nucleus	See Lateral hypothalamus § Function – primary source of orexin neurons that project throughout the brain and spinal cord
		Lateral tuberal nuclei
Posterior (mammillary)	Medial	Mammillary nuclei (part of mammillary bodies)	memory
		Posterior nucleus	Increase blood pressure pupillary dilation shivering vasopressin release
	Lateral	Lateral nucleus	See Lateral hypothalamus § Function – primary source of orexin neurons that project throughout the brain and spinal cord
		Tuberomammillary nucleus	arousal (wakefulness and attention) feeding and energy balance learning memory sleep

• 
  Cross-section of the monkey hypothalamus displays two of the major hypothalamic nuclei on either side of the fluid-filled third ventricle.
   
• 
  Hypothalamic nuclei 
   
• 
  Hypothalamic nuclei on one side of the hypothalamus, shown in a 3-D computer reconstruction

Connections

Further information: Lateral hypothalamus § Orexinergic projection system, and Tuberomammillary nucleus § Histaminergic outputs

The hypothalamus is highly interconnected with other parts of the central nervous system, in particular the brainstem and its reticular formation. As part of the limbic system, it has connections to other limbic structures including the amygdala and septum, and is also connected with areas of the autonomous nervous system.

The hypothalamus receives many inputs from the brainstem, the most notable from the nucleus of the solitary tract, the locus coeruleus, and the ventrolateral medulla.

Most nerve fibres within the hypothalamus run in two ways (bidirectional).

• Projections to areas caudal to the hypothalamus go through the medial forebrain bundle, the mammillotegmental tract and the dorsal longitudinal fasciculus.
• Projections to areas rostral to the hypothalamus are carried by the mammillothalamic tract, the fornix and terminal stria.
• Projections to areas of the sympathetic motor system (lateral horn spinal segments T1–L2/L3) are carried by the hypothalamospinal tract and they activate the sympathetic motor pathway.

Sexual dimorphism

Several hypothalamic nuclei are sexually dimorphic; i.e., there are clear differences in both structure and function between males and females. Some differences are apparent even in gross neuroanatomy: most notable is the sexually dimorphic nucleus within the preoptic area, in which the differences are subtle changes in the connectivity and chemical sensitivity of particular sets of neurons. The importance of these changes can be recognized by functional differences between males and females. For instance, males of most species prefer the odor and appearance of females over males, which is instrumental in stimulating male sexual behavior. If the sexually dimorphic nucleus is lesioned, this preference for females by males diminishes. Also, the pattern of secretion of growth hormone is sexually dimorphic; this is why in many species, adult males are visibly distinct sizes from females.

Responsiveness to ovarian steroids

Other striking functional dimorphisms are in the behavioral responses to ovarian steroids of the adult. Males and females respond to ovarian steroids in different ways, partly because the expression of estrogen-sensitive neurons in the hypothalamus is sexually dimorphic; i.e., estrogen receptors are expressed in different sets of neurons.

Estrogen and progesterone can influence gene expression in particular neurons or induce changes in cell membrane potential and kinase activation, leading to diverse non-genomic cellular functions. Estrogen and progesterone bind to their cognate nuclear hormone receptors, which translocate to the cell nucleus and interact with regions of DNA known as hormone response elements (HREs) or get tethered to another transcription factor's binding site. Estrogen receptor (ER) has been shown to transactivate other transcription factors in this manner, despite the absence of an estrogen response element (ERE) in the proximal promoter region of the gene. In general, ERs and progesterone receptors (PRs) are gene activators, with increased mRNA and subsequent protein synthesis following hormone exposure.

Male and female brains differ in the distribution of estrogen receptors, and this difference is an irreversible consequence of neonatal steroid exposure.^{[citation needed]} Estrogen receptors (and progesterone receptors) are found mainly in neurons in the anterior and mediobasal hypothalamus, notably:

• the preoptic area (where LHRH neurons are located, regulating dopamine responses and maternal behavior;
• the periventricular nucleus where somatostatin neurons are located, regulating stress levels;
• the ventromedial hypothalamus which regulates hunger and sexual arousal.

Development

Median sagittal section of brain of human embryo of three months

In neonatal life, gonadal steroids influence the development of the neuroendocrine hypothalamus. For instance, they determine the ability of females to exhibit a normal reproductive cycle, and of males and females to display appropriate reproductive behaviors in adult life.

• If a female rat is injected once with testosterone in the first few days of postnatal life (during the "critical period" of sex-steroid influence), the hypothalamus is irreversibly masculinized; the adult rat will be incapable of generating an LH surge in response to estrogen (a characteristic of females), but will be capable of exhibiting male sexual behaviors (mounting a sexually receptive female).
• By contrast, a male rat castrated just after birth will be feminized, and the adult will show female sexual behavior in response to estrogen (sexual receptivity, lordosis behavior).

In primates, the developmental influence of androgens is less clear, and the consequences are less understood. Within the brain, testosterone is aromatized (to estradiol), which is the principal active hormone for developmental influences. The human testis secretes high levels of testosterone from about week 8 of fetal life until 5–6 months after birth (a similar perinatal surge in testosterone is observed in many species), a process that appears to underlie the male phenotype. Estrogen from the maternal circulation is relatively ineffective, partly because of the high circulating levels of steroid-binding proteins in pregnancy.

Sex steroids are not the only important influences upon hypothalamic development; in particular, pre-pubertal stress in early life (of rats) determines the capacity of the adult hypothalamus to respond to an acute stressor. Unlike gonadal steroid receptors, glucocorticoid receptors are very widespread throughout the brain; in the paraventricular nucleus, they mediate negative feedback control of CRF synthesis and secretion, but elsewhere their role is not well understood.

Function

Hormone release

Endocrine glands in the human head and neck and their hormones

The hypothalamus has a central neuroendocrine function, most notably by its control of the anterior pituitary, which in turn regulates various endocrine glands and organs. Releasing hormones (also called releasing factors) are produced in hypothalamic nuclei then transported along axons to either the median eminence or the posterior pituitary, where they are stored and released as needed.

Anterior pituitary

In the hypothalamic–adenohypophyseal axis, releasing hormones, also known as hypophysiotropic or hypothalamic hormones, are released from the median eminence, a prolongation of the hypothalamus, into the hypophyseal portal system, which carries them to the anterior pituitary where they exert their regulatory functions on the secretion of adenohypophyseal hormones. These hypophysiotropic hormones are stimulated by parvocellular neurosecretory cells located in the periventricular area of the hypothalamus. After their release into the capillaries of the third ventricle, the hypophysiotropic hormones travel through what is known as the hypothalamo-pituitary portal circulation. Once they reach their destination in the anterior pituitary, these hormones bind to specific receptors located on the surface of pituitary cells. Depending on which cells are activated through this binding, the pituitary will either begin secreting or stop secreting hormones into the rest of the bloodstream.

Secreted hormone	Abbreviation	Produced by	Effect
Thyrotropin-releasing hormone (Prolactin-releasing hormone)	TRH, TRF, or PRH	Parvocellular neurosecretory cells of the paraventricular nucleus	Stimulate thyroid-stimulating hormone (TSH) release from anterior pituitary (primarily) Stimulate prolactin release from anterior pituitary
Corticotropin-releasing hormone	CRH or CRF	Parvocellular neurosecretory cells of the paraventricular nucleus	Stimulate adrenocorticotropic hormone (ACTH) release from anterior pituitary
Dopamine (Prolactin-inhibiting hormone)	DA or PIH	Dopamine neurons of the arcuate nucleus	Inhibit prolactin release from anterior pituitary
Growth-hormone-releasing hormone	GHRH	Neuroendocrine neurons of the Arcuate nucleus	Stimulate growth-hormone (GH) release from anterior pituitary
Gonadotropin-releasing hormone	GnRH or LHRH	Neuroendocrine cells of the Preoptic area	Stimulate follicle-stimulating hormone (FSH) release from anterior pituitary Stimulate luteinizing hormone (LH) release from anterior pituitary
Somatostatin (growth-hormone-inhibiting hormone)	SS, GHIH, or SRIF	Neuroendocrine cells of the Periventricular nucleus	Inhibit growth-hormone (GH) release from anterior pituitary Inhibit (moderately) thyroid-stimulating hormone (TSH) release from anterior pituitary

Other hormones secreted from the median eminence include vasopressin, oxytocin, and neurotensin.

Posterior pituitary

In the hypothalamic–pituitary–adrenal axis, neurohypophysial hormones are released from the posterior pituitary, which is actually a prolongation of the hypothalamus, into the circulation.

Secreted hormone	Abbreviation	Produced by	Effect
Oxytocin	OXY or OXT	Magnocellular neurosecretory cells of the paraventricular nucleus and supraoptic nucleus	Uterine contraction Lactation (letdown reflex)
Vasopressin (antidiuretic hormone)	ADH or AVP	Magnocellular and parvocellular neurosecretory cells of the paraventricular nucleus, magnocellular cells in supraoptic nucleus	Increase in the permeability to water of the cells of distal tubule and collecting duct in the kidney and thus allows water reabsorption and excretion of concentrated urine

It is also known that hypothalamic–pituitary–adrenal axis (HPA) hormones are related to certain skin diseases and skin homeostasis. There is evidence linking hyperactivity of HPA hormones to stress-related skin diseases and skin tumors.

Stimulation

The hypothalamus coordinates many hormonal and behavioural circadian rhythms, complex patterns of neuroendocrine outputs, complex homeostatic mechanisms, and important behaviours. The hypothalamus must, therefore, respond to many different signals, some of which are generated externally and some internally. Delta wave signalling arising either in the thalamus or in the cortex influences the secretion of releasing hormones; GHRH and prolactin are stimulated whilst TRH is inhibited.

The hypothalamus is responsive to:

• Light: daylength and photoperiod for regulating circadian and seasonal rhythms
• Olfactory stimuli, including pheromones
• Steroids, including gonadal steroids and corticosteroids
• Neurally transmitted information arising in particular from the heart, enteric nervous system (of the gastrointestinal tract), and the reproductive tract.
• Autonomic inputs
• Blood-borne stimuli, including leptin, ghrelin, angiotensin, insulin, pituitary hormones, cytokines, plasma concentrations of glucose and osmolarity etc.
• Stress
• Invading microorganisms by increasing body temperature, resetting the body's thermostat upward.

Olfactory stimuli

Olfactory stimuli are important for sexual reproduction and neuroendocrine function in many species. For instance if a pregnant mouse is exposed to the urine of a 'strange' male during a critical period after coitus then the pregnancy fails (the Bruce effect). Thus, during coitus, a female mouse forms a precise 'olfactory memory' of her partner that persists for several days. Pheromonal cues aid synchronization of oestrus in many species; in women, synchronized menstruation may also arise from pheromonal cues, although the role of pheromones in humans is disputed.

Blood-borne stimuli

Peptide hormones have important influences upon the hypothalamus, and to do so they must pass through the blood–brain barrier. The hypothalamus is bounded in part by specialized brain regions that lack an effective blood–brain barrier; the capillary endothelium at these sites is fenestrated to allow free passage of even large proteins and other molecules. Some of these sites are the sites of neurosecretion - the neurohypophysis and the median eminence. However, others are sites at which the brain samples the composition of the blood. Two of these sites, the SFO (subfornical organ) and the OVLT (organum vasculosum of the lamina terminalis) are so-called circumventricular organs, where neurons are in intimate contact with both blood and CSF. These structures are densely vascularized, and contain osmoreceptive and sodium-receptive neurons that control drinking, vasopressin release, sodium excretion, and sodium appetite. They also contain neurons with receptors for angiotensin, atrial natriuretic factor, endothelin and relaxin, each of which important in the regulation of fluid and electrolyte balance. Neurons in the OVLT and SFO project to the supraoptic nucleus and paraventricular nucleus, and also to preoptic hypothalamic areas. The circumventricular organs may also be the site of action of interleukins to elicit both fever and ACTH secretion, via effects on paraventricular neurons.

It is not clear how all peptides that influence hypothalamic activity gain the necessary access. In the case of prolactin and leptin, there is evidence of active uptake at the choroid plexus from the blood into the cerebrospinal fluid (CSF). Some pituitary hormones have a negative feedback influence upon hypothalamic secretion; for example, growth hormone feeds back on the hypothalamus, but how it enters the brain is not clear. There is also evidence for central actions of prolactin.

Findings have suggested that thyroid hormone (T4) is taken up by the hypothalamic glial cells in the infundibular nucleus/ median eminence, and that it is here converted into T3 by the type 2 deiodinase (D2). Subsequent to this, T3 is transported into the thyrotropin-releasing hormone (TRH)-producing neurons in the paraventricular nucleus. Thyroid hormone receptors have been found in these neurons, indicating that they are indeed sensitive to T3 stimuli. In addition, these neurons expressed MCT8, a thyroid hormone transporter, supporting the theory that T3 is transported into them. T3 could then bind to the thyroid hormone receptor in these neurons and affect the production of thyrotropin-releasing hormone, thereby regulating thyroid hormone production.

The hypothalamus functions as a type of thermostat for the body. It sets a desired body temperature, and stimulates either heat production and retention to raise the blood temperature to a higher setting or sweating and vasodilation to cool the blood to a lower temperature. All fevers result from a raised setting in the hypothalamus; elevated body temperatures due to any other cause are classified as hyperthermia. Rarely, direct damage to the hypothalamus, such as from a stroke, will cause a fever; this is sometimes called a hypothalamic fever. However, it is more common for such damage to cause abnormally low body temperatures.

Steroids

The hypothalamus contains neurons that react strongly to steroids and glucocorticoids (the steroid hormones of the adrenal gland, released in response to ACTH). It also contains specialized glucose-sensitive neurons (in the arcuate nucleus and ventromedial hypothalamus), which are important for appetite. The preoptic area contains thermosensitive neurons; these are important for TRH secretion.

Neural

Oxytocin secretion in response to suckling or vagino-cervical stimulation is mediated by some of these pathways; vasopressin secretion in response to cardiovascular stimuli arising from chemoreceptors in the carotid body and aortic arch, and from low-pressure atrial volume receptors, is mediated by others. In the rat, stimulation of the vagina also causes prolactin secretion, and this results in pseudo-pregnancy following an infertile mating. In the rabbit, coitus elicits reflex ovulation. In the sheep, cervical stimulation in the presence of high levels of estrogen can induce maternal behavior in a virgin ewe. These effects are all mediated by the hypothalamus, and the information is carried mainly by spinal pathways that relay in the brainstem. Stimulation of the nipples stimulates release of oxytocin and prolactin and suppresses the release of LH and FSH.

Cardiovascular stimuli are carried by the vagus nerve. The vagus also conveys a variety of visceral information, including for instance signals arising from gastric distension or emptying, to suppress or promote feeding, by signalling the release of leptin or gastrin, respectively. Again this information reaches the hypothalamus via relays in the brainstem.

In addition hypothalamic function is responsive to—and regulated by—levels of all three classical monoamine neurotransmitters, noradrenaline, dopamine, and serotonin (5-hydroxytryptamine), in those tracts from which it receives innervation. For example, noradrenergic inputs arising from the locus coeruleus have important regulatory effects upon corticotropin-releasing hormone (CRH) levels.

Control of food intake

Peptide hormones and neuropeptides that regulate feeding

Peptides that increase feeding behavior	Peptides that decrease feeding behavior
Ghrelin	Leptin
Neuropeptide Y	(α,β,γ)-Melanocyte-stimulating hormones
Agouti-related peptide	Cocaine- and amphetamine-regulated transcript peptides
Orexins (A,B)	Corticotropin-releasing hormone
Melanin-concentrating hormone	Cholecystokinin
Galanin	Insulin
	Glucagon-like peptide 1

The extreme lateral part of the ventromedial nucleus of the hypothalamus is responsible for the control of food intake. Stimulation of this area causes increased food intake. Bilateral lesion of this area causes complete cessation of food intake. Medial parts of the nucleus have a controlling effect on the lateral part. Bilateral lesion of the medial part of the ventromedial nucleus causes hyperphagia and obesity of the animal. Further lesion of the lateral part of the ventromedial nucleus in the same animal produces complete cessation of food intake.

There are different hypotheses related to this regulation:

1. Lipostatic hypothesis: This hypothesis holds that adipose tissue produces a humoral signal that is proportionate to the amount of fat and acts on the hypothalamus to decrease food intake and increase energy output. It has been evident that a hormone leptin acts on the hypothalamus to decrease food intake and increase energy output.
2. Gutpeptide hypothesis: gastrointestinal hormones like Grp, glucagons, CCK and others claimed to inhibit food intake. The food entering the gastrointestinal tract triggers the release of these hormones, which act on the brain to produce satiety. The brain contains both CCK-A and CCK-B receptors.
3. Glucostatic hypothesis: The activity of the satiety center in the ventromedial nuclei is probably governed by the glucose utilization in the neurons. It has been postulated that when their glucose utilization is low and consequently when the arteriovenous blood glucose difference across them is low, the activity across the neurons decrease. Under these conditions, the activity of the feeding center is unchecked and the individual feels hungry. Food intake is rapidly increased by intraventricular administration of 2-deoxyglucose therefore decreasing glucose utilization in cells.
4. Thermostatic hypothesis: According to this hypothesis, a decrease in body temperature below a given set-point stimulates appetite, whereas an increase above the set-point inhibits appetite.

Fear processing

The medial zone of hypothalamus is part of a circuitry that controls motivated behaviors, like defensive behaviors. Analyses of Fos-labeling showed that a series of nuclei in the "behavioral control column" is important in regulating the expression of innate and conditioned defensive behaviors.

Antipredatory defensive behavior

Exposure to a predator (such as a cat) elicits defensive behaviors in laboratory rodents, even when the animal has never been exposed to a cat. In the hypothalamus, this exposure causes an increase in Fos-labeled cells in the anterior hypothalamic nucleus, the dorsomedial part of the ventromedial nucleus, and in the ventrolateral part of the premammillary nucleus (PMDvl). The premammillary nucleus has an important role in expression of defensive behaviors towards a predator, since lesions in this nucleus abolish defensive behaviors, like freezing and flight.  The PMD does not modulate defensive behavior in other situations, as lesions of this nucleus had minimal effects on post-shock freezing scores. The PMD has important connections to the dorsal periaqueductal gray, an important structure in fear expression. In addition, animals display risk assessment behaviors to the environment previously associated with the cat. Fos-labeled cell analysis showed that the PMDvl is the most activated structure in the hypothalamus, and inactivation with muscimol prior to exposure to the context abolishes the defensive behavior. Therefore, the hypothalamus, mainly the PMDvl, has an important role in expression of innate and conditioned defensive behaviors to a predator.

Social defeat

Likewise, the hypothalamus has a role in social defeat: Nuclei in medial zone are also mobilized during an encounter with an aggressive conspecific. The defeated animal has an increase in Fos levels in sexually dimorphic structures, such as the medial pre-optic nucleus, the ventrolateral part of ventromedial nucleus, and the ventral premammilary nucleus. Such structures are important in other social behaviors, such as sexual and aggressive behaviors. Moreover, the premammillary nucleus also is mobilized, the dorsomedial part but not the ventrolateral part. Lesions in this nucleus abolish passive defensive behavior, like freezing and the "on-the-back" posture.

Learning arbitrator

Recent research has questioned whether the lateral hypothalamus's role is only restricted to initiating and stopping innate behaviors and argued it learns about food-related cues. Specifically that it opposes learning about information what is neutral or distant to food. According this view, the lateral hypothalamus is "a unique arbitrator of learning capable of shifting behavior toward or away from important events".

Septal area

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Septal_area

 

Septal area
Lateral and medial septal nuclei in the septal area of the mouse brain
Details
Identifiers
Latin	nuclei septales
MeSH	D012686
NeuroNames	259
TA98	A14.1.09.266
TA2	5548
FMA	61845

The septal area (medial olfactory area), consisting of the lateral septum and medial septum, is an area in the lower, posterior part of the medial surface of the frontal lobe, and refers to the nearby septum pellucidum.

The septal nuclei are located in this area. The septal nuclei are composed of medium-size neurons which are classified into dorsal, ventral, medial, and caudal groups. The septal nuclei receive reciprocal connections from the olfactory bulb, hippocampus, amygdala, hypothalamus, midbrain, habenula, cingulate gyrus, and thalamus. The septal nuclei are essential in generating the theta rhythm of the hippocampus.

The septal area (medial olfactory area) has no relation to the sense of smell, but it is considered a pleasure zone in animals. The septal nuclei play a role in reward and reinforcement along with the nucleus accumbens. In the 1950s, Olds & Milner showed that rats with electrodes implanted in this area will self-stimulate repeatedly (e.g., press a bar to receive electric current that stimulate the neurons). Experiments on the septal area of humans have taken place since the 1960s.

Connections

Detail of drawing showing components of septal area below corpus callosum.

The septal area is located on the lower posterior part of the frontal lobe. The septal area refers to the nearby septum pellucidum. It is located underneath the corpus callosum and in front of the lamina terminalis. The lamina terminalis is a layer of gray matter that connects the optic chiasma and the anterior commissure. The septal nuclei in the septal area are essential in generating the theta rhythm of the hippocampus.

The dorsal septum projects to the lateral preoptic area, lateral hypothalamus, periventricular hypothalamus and midline thalamus.

Fibers from the ventral half of the septum project topographically to the hippocampal formation, thalamus, hypothalamus and midbrain. Specifically, neurons located along the midline in the vertical limb of the diagonal band of Broca project through the dorsal fornix to all CA fields of the dorsal hippocampus and adjacent subicular cortex. Other fibers from this region project through the stria medullaris to the medial and lateral habenular nuclei, the paratenial and anteromedial nucleus of the thalamus, and through the medial forebrain bundle to the pars posterior of the medial mammillary nucleus.

Cells located in the intermediolateral septum also project through the lateral part of the fimbria to all CA fields of the ventral hippocampus and adjacent subicular and entorhinal cortices. These cells also send fibers through the stria medullaris to the lateral habenular nucleus and mediodorsal thalamic nucleus. Other axons arising from these cells descend through the medial forebrain bundle to terminate in a region dorsal to the interpeduncular nucleus.

The lateral septum is a relay center for connections from the CA3 of the hippocampus to the ventral tegmental area. These connections help link reward signals with the context in which they occur.

Fibers from the most lateral part of the ventral septum (i.e., bed nucleus of the anterior commissure) project through the stria terminalis to the ventral subiculum. In addition, cells located in the horizontal limb of the diagonal band project massively to the pars posterior of the medial mammillary nucleus, the ventral tegmental area, and amygdala.

Functions of the lateral septum

The lateral septum and movement and reward

The lateral septum is involved in a variety of functions, including emotional, motivational, and spatial behavior. It has been suggested that the LS may regulate interactions between the hippocampus and other regions that mediate goal directed behavior, such as the ventral tegmental area. Firing of LS neurons is modulated by both speed and acceleration  and spatial location, and that firing is also related to reward and context. It has thus been suggested that the lateral septum may incorporate movement into the evaluation of environmental context with respect to motivation and reward.

Lateral septum and social behavior

Inhibitory GABA, and excitatory glutamate, which regulate lateral septum (LS) activity, have been found to be increased during social play in juvenile rats. No sex differences were found in extracellular GABA concentrations during social playing, however, glutamate plays a major role in female social playing. When glutamate receptors are blocked in the LS pharmacologically, there is a significant decrease in female social playing, while males had no decrease in playing. This suggests that in the lateral septum, GABA neurotransmission is involved in social play behavior regulation in both sexes, while glutamate neurotransmission is sex-specific, involved in regulation of social play only in female juvenile rats.

Lateral septum and reproduction

Experiments have shown that both testosterone and dihydrotestosterone, when implanted directly into the lateral septum of male rats, caused a significant rise in serum LH and FSH levels, while not significantly increasing serum testosterone and dihydrotestosterone levels respectively. This indicates that the effect is occurring through testosterone receptors and independently of conversion to estrogen via aromatization. As of now, it is unclear, what exact pathway is mediating this phenomenon. Septal lesions significantly decreased serum LH and testosterone levels in male rats, while FSH and prolactin production were unaffected by the surgery. Electrical stimulation of the septum induced the elevation of serum LH and FSH levels. These data suggest that the lateral and/or the medial septum may play a role in the control of GnRH/gonadotropin secretion, and thus, the reproductive axis.

Lateral septum and memory

Despite the diverse direct projection system between the hippocampus and the lateral septum, the first pieces of evidence regarding the role of latter brain area in memory formation and retention have only started to emerge as of 2022. However, recent research has started to shed light on the potentially diverse roles of the lateral septum.

Social memory

The roles of the lateral septum in formation of social memories remain unclear and controversial. It is clear, that some role is being played, as oxytocin and vasopressin, when administered into the lateral septum after social training were able to enhance memory formation, while their respective receptor blockers had the opposite effect. However, data on effects of pre-training administration of these compounds is mixed, hence the lack of consensus.

Fear memory

Pieces of evidence suggesting the role the lateral septum could be playing in fear memory formation and consolidation have started emerging at the end of the XX. century. Inhibitory avoidance tasks using footshock chambers on mice were deployed to study the effects of the disruption of the lateral septum and hippocampal inputs on fear memory formation and retrieval respectively. In both cases, fear memory formation/retrieval was impaired, supporting the hypothesis that hippocampal projections to the lateral septum are at least in part responsible for these mechanisms. The lateral septum could also prove essential in fear memory consolidation. Post-shock adminitration of CRF into the lateral septum enhanced fear memory in the relelvant context; however, this finding still needs to be supported by further studies.