Hippocampal interneurons are direct targets for circulating glucocorticoids

Abstract

The hippocampus has become a significant target of stress research in recent years because of its role in cognitive functioning, neuropathology, and regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Despite the pervasive impact of stress on psychiatric and neurological disease, many of the circuit-and cell-dependent mechanisms giving rise to the limbic regulation of the stress response remain unknown.Hippocampal excitatory neurons generally express high levels of glucocorticoid receptors (GRs) and are therefore positioned to respond directly to serum glucocorticoids. These neurons are, in turn, regulated by neighboring interneurons, subtypes of which have been shown to respond to stress exposure. However, GR expression among hippocampal interneurons is not well characterized. To determine whether key interneuron populations are direct targets for glucocorticoid action, we used two transgenic mouse lines to label parvalbumin-positive (PV+) and somatostatin-positive (SST+) interneurons. GR immunostaining of labeled interneurons was characterized within the dorsal and ventral dentate hilus, dentate cell body layer, and CA1 and CA3 stratum oriens and stratum pyramidale. While nearly all hippocampal SST+ interneurons expressed GR across all regions, GR labeling of PV+ interneurons showed considerable subregion variability. The percentage of PV+, GR+ cells was highest in the CA3 stratum pyramidale and lowest in the CA1 stratum oriens, with other regions showing intermediate levels of expression. Together, these findings indicate that, under baseline conditions, hippocampal SST+ interneurons are a ubiquitous glucocorticoid target, while only distinct populations of PV+ interneurons are direct targets. This anatomical diversity suggests functional differences in the regulation of stress-dependent hippocampal responses.

Chronic stress causes striatal disinhibition mediated by SOM-interneurons in male mice

“…What makes striatal SOM (but not PV) interneurons direct targets of chronic stress is still an open question. In the hippocampus, for example, it has been shown that SOM interneurons express high levels of glucocorticoid receptors (GRs), being well positioned to respond directly to circulating glucocorticoids, while only distinct populations of PV interneurons are direct targets 69 . However, careful consideration should be taken when extrapolating findings from one brain region to another.…”

Serum cortisol and insulin-like growth factor 1 levels in major depressive disorder and schizophrenia

“…Moreover, magnetic resonance imaging studies have shown that hippocampal volume is lower in patients with schizophrenia than in patients with MDD 44 . GRs suppress cortisol secretion via negative feedback on the HPA system 42 ; thus, cortisol may be higher in patients with schizophrenia. Furthermore, given that peripheral cortisol secretion and brain dopamine release are positively correlated 61 , 62 , cortisol may be higher in schizophrenia patients with excessive dopamine secretion in the brain.…”

“…The impairment of negative feedback mechanisms in response to increased cortisol is common in patients with schizophrenia and MDD 42 , 43 . The levels of glucocorticoid receptors (GRs) in the hippocampus, which are involved in the negative feedback mechanisms that respond to increased cortisol, are lower in schizophrenia patients than in MDD patients 43 , 44 .…”

“…Therefore, we hypothesized that IGF-1 would commonly be increased to compensate for the deficits in neuroplasticity and myelin formation that underlie schizophrenia and MDD 10 , 32 , 44 , 46 – 48 . Furthermore, because stress and cortisol secretion are positively correlated 49 , 50 , we hypothesized that cortisol levels would be correlated with the symptom severity of MDD and schizophrenia and reflect the impairment of negative feedback mechanisms in response to the increased cortisol in the two disorders 42 , 43 . Moreover, IGF-1 levels may be correlated with the symptom severity of the two disorders to compensate for the decrease in neuroplasticity and myelination as symptoms worsen 51 , 52 .…”

Hippocampal glucocorticoid receptors modulate status epilepticus severity

“…Fluorescence intensity was used to determine the percentage of GR immunoreactive neurons in each group. GR immunopositive cells were defined as being 2× background fluorescence intensity ( Kraus et al, 2022 ). Background intensity was set as the mean fluorescence intensity of mCherry+ cells in no-primary control slices (GR antibody left out).…”