The human hypothalamus in mood disorders: The HPA axis in the center

Abstract

There are no specific structural neuropathological hallmarks found in the brain of mood disorders. Instead, there are molecular, functional and structural alterations reported in many brain areas. The neurodevelopmental underpinning indicated the presence of various genetic and developmental risk factors. The effect of genetic polymorphisms and developmental sequalae, some of which may start in the womb, result in functional changes in a network mediated by neurotransmitters and neuropeptides, which make the emotion- and stress-related brain systems more vulnerable to stressful events. This network of stress-related neurocircuits consists of, for instance, brainstem nuclei, the amygdala, habenula, prefrontal cortex and hypothalamus. Various nuclei of the hypothalamus form indeed one of the crucial hubs in this network. This structure concerns not only the hypothalamo-pituitary-adrenal (HPA) axis that integrate the neuro-endocrine-immune responses to stress, but also other hypothalamic nuclei and systems that play a key role in the symptoms of depression, such as disordered day-night rhythm, lack of reward feelings, disturbed eating, sex, and disturbed cognitive functions. The present review will focus on the changes in the human hypothalamus in depression, with the HPA axis in the center. We will discuss the inordinate network of neurotransmitters and neuropeptides involved, with the hope to find the most vulnerable neurobiological systems and the possible development of tailor-made treatments for mood disorders in the future.

Keywords: GABA; Glutamate; Neuropeptide; Sex differences; The hypothalamo-pituitary-adrenal axis.

Fig. 1

Schematic illustration of some of the key mechanisms that may cause a mood disorder by impaired input of neurotransmitters (monoamines and amino acids) and/or neuropeptides (arginine vasopressin (AVP), oxytocin (OXT)) on the hypothalamo–pituitary– adrenal (HPA) axis. In the control situation (normal mood), the corticotropinreleasing hormone (CRH) neurons of the stress axis (HPA axis) are inhibited by a γ-aminobutyric acid (GABA)-ergic input from (extra-)hypothalamic areas and by an AVP input from the suprachiasmatic nucleus (SCN). Some monoamines and neuropeptides (e.g., OXT) also inhibit the HPA axis. When there is depression, the HPA axis is activated by: (1) diminished GABAergic input; and/or (2) increased glutaminergic input from (extra-)hypothalamic sites; and/or (3) diminished inhibition by the SCN; and/or (4) stimulatory influence on the HPA axis by alterations in the monoamine or neuropeptide input; and/or (5) a deficient cortisol feedback effect due to the presence of glucocorticoid resistance. The resulting disinhibition of the paraventricular nucleus (PVN) causes a chronic rise in CRH and cortisol levels in depression, which causes mood changes through their action on the brain. The hyperactivity of the HPA axis may be due to a multitude of risk factors such as genetic polymorphisms, development sequelae, and environmental factors. A decreased amount of AVP mRNA of the SCN was found in depression, which seems to be the basis of the impaired circadian regulation of the HPA system in depression and a decreased inhibition of CRH neurons. Arrow: stimulation; Bar with ball-head: inhibition. The thickness of the lines indicates the strength of the effects. ACTH, adrenocorticotropic hormone. Modified from Fig. 1 of (Bao et al., 2012).