Case 1 - HPA hypothesis of MDD Flashcards
HPA axis
The hypothalamic-pituitary-adrenal axis (HPA) is the main stress response system, and it is the link between perceived stress and physiological reactions to stress
–> fight or flight
an acute stressor and the resulting stress response may constitute an adaptive mechanism of our endocrine system with mostly protective effects, whereas repetitive and sustained stress may entail harmful changes
HPA axis hormones
1) Activation of the HPA axis with an increased production of corticotropin-releasing hormone (CRH) in the hypothalamus, which stimulates the production and secretion of the adrenocorticotropic hormone (ACTH) from the pituitary cells.
2) Synthesis and excretion of glucocorticoids (GCs), like cortisol, from the adrenal cortex.
a) Cortisol has various effects on the body to help in dealing with the stressor: it increases BP and cardiac output, it increases circulating glucose levels, etc.
i) In a negative feedback loop, sufficient cortisol inhibits the release of both ACTH and CRH.
central regulation of HPA
- The hippocampus, known for its role in memory and spatial navigation, is instrumental in negative feedback regulation. It contains a high concentration of glucocorticoid receptors (GRs) and acts to inhibit the further release of corticotropin-releasing hormone (CRH) from the hypothalamus when activated by cortisol
- The amygdala, a center for emotional processing and fear response, plays a pivotal role in initiating the stress response. Upon perceiving a threat, the amygdala signals the hypothalamus (CRF) to activate the HPA axis, resulting in cortisol release. It also interacts with the hippocampus and prefrontal cortex to modulate stress response regulation.
- The prefrontal cortex, particularly its ventromedial and dorsolateral regions, governs executive functions such as decision-making and emotion regulation. It exerts top-down control over lower brain regions involved in stress response, including the amygdala and hypothalamus. Through connections with these structures, the prefrontal cortex provides inhibitory input, modulating their activity and influencing HPA axis regulation
dysregulation in central control areas
⇾ Chronic stress may lead to structural changes in the hippocampus, impairing its regulatory function and contributing to stress-related disorders.
i. Dendritic atrophy
ii. Decreased neurogenesis
iii. Decreases volume
⇾ Dysregulation of the amygdala is implicated in conditions like anxiety disorders and PTSD.
Dysfunction of the prefrontal cortex, such as deficits in cognitive control or impairments in emotion regulation, may contribute to maladaptive stress responses and increase vulnerability to stress-related psychiatric disorders
GR and MR - general
- In the brain, glucocorticoids act through two receptors:
o the high affinity mineralocorticoid receptor (MR)
o the lower affinity glucocorticoid receptor (GR).
Both are nuclear receptors that belong to the same family of intracellular ligand-dependent transcription factors: Nuclear receptors modulate the transcription of genes in direct response to small lipophilic ligands. - Given its high affinity, MR is occupied at basal hormone levels, whereas GR is activated at the circadian peak of glucocorticoid secretion and during stress
- MR = limbic (mainly)
- GR more widespread
–> both involved in cognition, memory and stress
GR and MR actions
- GR and MR control a wide range of processes, ranging from neuronal differentiation [8] and excitability [9] to behavioral reactivity, mood, and cognition [2]—all processes that are needed to adapt to acute or chronic stress.
o MR activation during the early phases of acute stress is important in the appraisal process and memory retrieval
o GR complements this by promoting memory consolidation and behavioral adaptation [2].
- In addition to complementary actions of GR and MR, they can also exert opposing effects, even within the same cell type.
–> MR pro-inflamm
GR anti-inflamm
–> overaction GR and underaction MR (loss of tonic HPA inhibition leading to chronic activity)–> SZ
GR signalling
GCs are derived from cortisol and produced by the adrenal medulla under control of the HPA-axis
- Glucocorticoid Receptor Signaling.
1. Upon binding glucocorticoids, cytoplasmic GR undergoes a confirmational change
2. Becomes hyperphosphorylated (P)
3. Dissociates from accessory proteins
4. Translocates into the nucleus and homodimerizes
5. Exerts its actions through genomic mechanisms
a. In the nucleus, GR enhances or represses transcription of target genes by:
1. direct binding to simple or negative GREs
2. tethering itself to other transcription factors
3. direct binding to GRE and interacting with other transcription factors.
b. rapid non genetic actions
circadian rhythm (pulsatile release, CORT response, awakening)
generated by a central clock in the suprachiasmatic nucleus (SCN) of the ventral hypothalamus, whose activity is regulated by light input received from the retina.
o A network of positive and negative transcriptional, translational and posttranslational feedback loops regulates the rhythmic transcription of circadian clock genes, leading to the expression of their protein products.
- The circadian rhythm of the HPA axis is governed by the SCN, which regulates glucocorticoid release by modulating CRH release from PVN neurons
- PULSATILE RELEASE: The circadian rhythm of the HPA axis is characterized by a pulsatile release of glucocorticoids from the adrenal gland that results in rapid ultradian oscillations of hormone levels both in the blood and within target tissues, including the brain (with a periodicity of 1 hour).
o These pulsatile dynamics are essential for optimal HPA responses; the presence of pulsatile glucocorticoid treatment triggers the interaction between MR and GR, leading to enhanced GR activity. - CORT-RESPONSE: Refers to the physiological reaction of the body to changes in cortisol levels.
o Stress perception → HPA activation → cortisol release → physiological changes → negative feedback loop.
o CORT circadian rhythm, including a reduced quiescent time for secretion and phase advancement of the rhythm. - AWAKENING RESPONSE: The cortisol awakening response (CAR) is a period of increased cortisol secretory activity initiated by morning awakening and typically peaking between 30 and 45 min post awakening.
It is under the influence of the suprachiasmatic nucleus (SCN) master clock
cortisol in MDD
- Elevated cortisol levels and increased inflammation have frequently been reported in patients with depression (particularly in treatment-resistant patients).
- The HPA axis is strictly implicated in inflammation.
o Its activation triggers the release of glucocorticoids, mainly cortisol in humans, which plays a crucial role in anti-inflammatory and immunosuppressive processes. - The currently accepted ‘glucocorticoid resistance’ model posits this increased inflammation as a consequence of reduced sensitivity to cortisol’s putative anti-inflammatory action.
o The ‘glucocorticoid resistance’ theory proposes that the glucocorticoid receptor (GR) is less sensitive to cortisol and does not bind as effectively; thus, the regulation of the HPA axis through negative feedback inhibition becomes impaired, resulting in continued activation and production of the axis components.
o This diminished sensitivity of the GR is considered to be due to reduced GR function and expression that has been reported in depression.
o Immune cells, which express GR, become less sensitive to cortisol’s ‘physiological anti-inflammatory action that may lead to increased inflammation that is observed in MDD
o Studies reported reduced function and/or expression of the GR in the immune cells of depressed patients
DEXA supression test
- The dexamethasone suppression test (DST) is a valuable diagnostic tool utilized in assessing, diagnosing and differentiating abnormalities within the HPA-axis, particularly in conditions marked by irregular cortisol production or secretion patterns, and may guide appropriate therapeutic interventions.
1. A baseline measurement of cortisol levels is obtained, typically through blood, saliva, or urine samples.
2. A synthetic glucocorticoid called dexamethasone is administered to the patient.
3. Cortisol levels are measured again at a specified time point, often either 8 or 24 hours later.
4. In individuals with normal HPA axis function, dexamethasone effectively suppresses cortisol production through negative feedback inhibition at the hypothalamus and pituitary gland.
o Consequently, cortisol levels should notably decrease compared to baseline levels.
o A cortisol level below a predetermined threshold is considered indicative of a normal suppression response.
o However, if cortisol levels fail to suppress adequately after dexamethasone administration, it suggests dysfunction or dysregulation within the HPA axis.
This lack of suppression is commonly observed in conditions such as depression, where alterations in HPA axis function may occur.
