Depression and Chronic Stress: Where’s the Negative Feedback? New Stress Response Pattern Found in Hypothalamus

Do Stress Activation Receptors Increase Rather Than Decrease in Chronic Stress as Experienced by Those who are Clinically Depressed?

Newly-discovered nerve cells a small, previously unknown group of nerve cells in the Paraventricular Nucleus, or PVN, within the hypothalamus – a part of the brain involved in regulating many of the body’s reactions express a receptor, CRFR1, on their outer walls, which enables them to take in the message of the CRF neurotransmitter — react in a manner that appears to be counterproductive when faced with chronic stress.

The hypothalamic–pituitary–adrenal axis is a pivotal component of an organism’s response to stressful challenges, and dysfunction of this neuroendocrine axis is associated with a variety of physiological and psychological pathologies.

The corticotropin-releasing factor type 1 receptor within the paraventricular nucleus of the hypothalamus is an important central component of hypothalamic–pituitary–adrenal axis regulation that prepares the organism for successive exposure to stressful stimuli.

The cortisol, along with the regular stress response, lowers the production of CRF, thus causing a negative feedback loop in which the mechanism slows down and stops.

In addition to the classic stress response in our bodies – an acute reaction that gradually abates when the threat passes – our bodies appear to have a separate mechanism that deals only with chronic stress.

In this research they discovered nerve cells express a receptor, CRFR1, on their outer walls  , which enables them to take in the message of the CRF neurotransmitter.

The scientists’ experiments showed that, in mice, the cortisol actually INCREASES the NUMBER CRFR1 receptors on these nerve cells, suggesting a positive feedback loop that could be self-renewing, rather than abating

Researchers pinpoint new neural mechanism that regulates chronic stress response

Paraventricular nucleus (PVN) CRFR1+ neurons represent a distinct population of hypothalamic neurons, which are functionally recruited only following prior exposure to chronic stress. 

While the negative feedback of GCs on PVN CRF expression is a fundamen- tal characteristic of HPA axis regulation, here we demonstrate positive feedback from GCs on PVN CRFR1 expression


In addition, PVN CRFR1 plays a role in modulating HPA axis activity, specifically under chronic stress conditions, by preparing the organism for subsequent exposure to stressful stimuli .

CRF plays an essential and well-established role in the regulation of the HPA axis both under ‘basal’ and stressful conditions Upon reaching the anterior pituitary, CRF stimulates adrenocorticotropic hormone release into the peripheral blood stream.

In turn, adrenocorticotropic hormone initiates the secretion of glucocorticoids (GCs; corticosterone (CORT) in rodents and cortisol in humans) from the adrenal cortex.

GCs, via the glucocorticoid and mineralocorticoid receptors (GR and MR), are fundamental peripheral and central transcriptional regulators in the response to stressful challenges.

In addition, they provide negative feedback at multiple levels of the HPA axis .

CRF induces its effects by activating two receptors: CRF receptor type 1 (CRFR1) and CRF receptor type 2 (CRFR2) CRFR1 is widely expressed in the mammalian brain and pituitary and is required for HPA axis activation

The CRF type 1 receptor (CRFR1) gene encodes one functional variant (α) in humans and rodents along with several nonfunctional splice variants

.The CRF type 2 receptor (CRFR2) has three functional splice variants in human (α, β, and γ) and two in rodents (α and β) resulting from the use of alternate 5′ starting exons.

CRFR1 is expressed at high levels in the brain and pituitary and low levels in peripheral tissues. The highest levels of CRFR1 expression are found in the anterior pituitary, olfactory bulb, cerebral cortex, hippocampus, and cerebellum. In peripheral tissues, low levels of CRFR1 are found in the adrenal gland, testis, and ovary.

In contrast, CRFR2 is highly expressed in peripheral tissues and localized in a limited number of nuclei in the brain.

Corticotropin-releasing factor type 2 receptors (CRFR2) are suggested to facilitate successful recovery from stress to maintain mental health.  The CRF type 2β variant is expressed in the periphery and is concentrated in the heart, skeletal muscle, skin, and the gastrointestinal tract.


Notably, CRFR1 is also expressed in the Paraventricular nucleus PVN of humans, and, even more notably, its expression has been found to be elevated in depressed patients .

Future studies are needed to explore the involvement of PVN CRFR1 in stress-related neuroendocrine and psychiatric disorders.Some studies have shown that patients suffering from depression have more of this receptor than average,”

The actual research is linked here:

Hypothalamic CRFR1 is essential for HPA axis regulation following chronic stress


In the well-known acute stress response, the neurotransmitter corticotrophin releasing factor (CRF) is released from the PVN and goes to the pituitary gland.

The neuroendocrine properties of CRF are mediated through CRFRl in the anterior pituitary.The pituitary gland releases hormones that then cause the adrenal gland to flood the bloodstream with the “stress hormone” cortisol. Binding of CRF to the type 1 receptor results in the stimulation of adenylate cyclase and a subsequent activation of cAMP pathway events that culminate with the release of ACTH from pituitary corticotropes

When they removed the adrenal glands of these mice, thus preventing the production of cortisol, the receptors did not appear on the PVN nerve-cell walls, while injecting synthetic stress hormones caused them to appear and restart the chain reaction.

These Weizmann Institute of Science findings, which recently appeared in Nature Neuroscience, may lead to better diagnosis of and treatment for anxiety and depression.
The experiments showed that in mice the cortisol actually increases the number of CRFR1 receptors on these nerve cells, suggesting a positive feedback loop that could be self-renewing, rather than abating.

This suggests that PVN CRFR1 was not required for the regulation of HPA axis activity under acute stress conditions but that PVN CFR1 action was essential for HPA axis function following chronic stress.

Activation of CRFR2 affects anxiety-like behaviour under stressed conditions and CRFR2-null mice have an anxiogenic phenotype, consistent with their role in providing negative feedback to cortisol.

If there is some balancing deviation between the CRFR2 and CRFR1 receptors the anxiogenic response to the lack of CRFR2 might also be implicated in the chronic stress associated with the increase in CRFR1 receptors.


On the other hand “the CRFR1 system is a separate one that evolved to deal with chronic stress.” Chen adds: “Some studies have shown that patients suffering from depression have more of this receptor than average, and this suggests further avenues of research and even ways to treat, in the future, disorders that arise from chronic stress.”

They compared mice genetically engineered to lack the receptor with a control group and exposed them to different kinds of stress, testing the hormones in their blood afterward.

When the mice experienced acute stress, both groups reacted in a similar manner, and their hormone levels were also similar. But chronic stressors told a different story: The genetically engineered mice stayed calmer and had lower levels of the cortisol-like hormone.

We found that PVN CRFR1+ neurons represented a distinct neuronal population residing in the PVN that did not colocalize with classical PVN markers such as CRF, arginine vasopressin, oxytocin or other parvocellular neurosecretory neuronal populations

NOTE: When we observe that this mechanism is one which the more adaptive mode of negative feedback intervening at some reasonable time when there is exposure to acute stress does not occur but instead the CRFR1 receptors increase and cause more activation rather than the CRFR2 receptors predominating and leading to less ongoing stress activation, we have to wonder about what role the Mineralocorticoid receptors play in this maladaptive insufficiency of negative feedback.

For more background on this interaction between MR receptors and CR receptors and their common function see our  own review of numerous studies here:

Stress Major Depression and Neurogenesis and the role of Brain MineraloCorticoid Receptors

When stress exposure activates the HPA-axis and results in the release of corticosteroids they actually  bind to two very different receptor types in the brain: the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR), which evolve from the same ancient receptor.

While the role of the GR in stress reactivity has been extensively studied, the MR still has not received adequate attention.  Nevertheless, pioneering in-depth studies over the past two decades have shown the importance of the brain MR in the processing of stressful information.

This action exerted by the stress hormones is mediated by mineralocorticoid receptors (MRs), which are expressed abundantly in the limbic circuitry, particularly in the hippocampus.  They thus provide a possible connecting path between cognitive processing of events via the limbic system and hippocampus as it might then impact on the hypothalamic production of stress related glucocorticoids   It is known as well that increased MR activity inhibits hypothalamic-pituitary-adrenal axis activity, promotes slow wave sleep, reduces anxiety and switches circuit connectivity to support coping  Limbic MR is down-regulated by chronic stress and during depression but induced by antidepressants.

Stress and Depression: a Crucial Role of the Mineralocorticoid Receptor.

A membrane-bound MR mediating the rapid effects of cortisol was recently discovered.  And indeed Mineralocorticoid receptors have a higher affinity for cortisol than they do for the CR receptors and indeed a greater affinity, as well, than the CR receptors do for their namesake hormones.  They are thus  the first receptors to encounter the effects of stress and are now considered to play a key role  stress resilience.

Both preclinical and clinical studies suggest that the MR is an important stress modulator and influences basal as well as stress-induced HPA-axis activity, stress appraisal, and fear-related memories. These MR effects are mediated by both genomic and non-genomic MRs and appear to be at least partially sex-dependent.

The brain mineralocorticoid receptor and stress resilience.

The majority of studies indicate that high MR functionality or expression may confer resilience to traumatic stress. This has direct clinical implications. First, increasing activity or expression of brain MRs may prevent or reverse symptoms of stress-related depression. Second, individuals with a relatively low MR functionality may possess an increased stress susceptibility for depression.

We have to thus wonder just what might be the connection between this finding of diminished negative feedback and increased positive feedback to stress as manifested to the variance in membrane bound CRFreceptor production and how that relates to the findings that diminished MR receptor function is also related to such lack of ‘resilience” and to risk of depression.


Increased anxiety in corticotropin-releasing factor type 2 receptor-null mice requires recent acute stress exposure and is associated with dysregulated serotonergic activity in limbic brain areas


Corticotropin-releasing factor type 2 receptors (CRFR2) are suggested to facilitate successful recovery from stress to maintain mental health. They are abundant in the midbrain raphe nuclei, where they regulate serotonergic neuronal activity and have been demonstrated to mediate behavioural consequences of stress. Here, we describe behavioural and serotonergic responses consistent with maladaptive recovery from stressful challenge in CRFR2-null mice.

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