Chronic stress induces cell type-selective transcriptomic and electrophysiological changes in the bed nucleus of the stria terminalis

Abstract

Distinct regions and cell types in the anterolateral group of the bed nucleus of the stria terminalis (BNST ALG) act to modulate anxiety in opposing ways. A history of chronic stress increases anxiety-like behavior with lasting electrophysiological effects on the BNST ALG. However, the opposing circuits within the BNST ALG suggest that stress may have differential effects on the individual cell types that comprise these circuits to shift the balance to favor anxiogenesis. Yet, the effects of stress are generally examined by treating all neurons within a particular region of the BNST as a homologous population. We used patch-clamp electrophysiology and single-cell quantitative reverse transcriptase PCR (scRT-PCR) to determine how chronic shock stress (CSS) affects electrophysiological and neurochemical properties of Type I, Type II, and Type III neurons in the BNST ALG. We report that CSS resulted in changes in the input resistance, time constant, action potential waveform, and firing rate of Type III but not Type I or II neurons. Additionally, only the Type III neurons exhibited an increase in Crf mRNA and a decrease in striatal-enriched protein tyrosine phosphatase (Ptpn5) mRNA after CSS. In contrast, only non-Type III cells showed a reduction in calcium-permeable AMPA receptor (CP-AMPAR) current and changes in mRNA expression of genes encoding AMPA receptor subunits after CSS. Importantly, none of the effects of CSS observed were seen in all cell types. Our results suggest that Type III neurons play a unique role in the BNST ALG circuit and represent a population of CRF neurons particularly sensitive to chronic stress.

Brain-Derived Neurotrophic Factor/Tropomyosin Receptor Kinase B Signaling Controls Excitability and Long-Term Depression in Oval Nucleus of the BNST

“…Further, in addition to differences in their physiology, ovBNST neurons can be genetically subdivided. For instance, the majority of type III neurons were found to express mRNA transcripts for CRF and to exhibit unique ion channel expression patterns (Hazra et al, 2011;Dabrowska et al, 2013), and both electrophysiological properties and CRF mRNA expression were altered exclusively in type III neurons in an animal model of chronic stress (Daniel et al, 2019). Here, we show a BDNF-mediated membrane hyperpolarization and decrease in spike activity in ovBNST neurons, with no apparent differences among the three different subclasses.…”

“…Moreover, most neurons in ovBNST express CRF (Dabrowska et al, 2013). Chronic stress indeed altered electrophysiological properties and CRF mRNA expression in a specific subclass of BNST neurons (Daniel et al, 2019), and chronic variable mild stress induced maladaptive behaviors through the activation of CRF signaling associated with a decrease in membrane K 1 current in ovBNST neurons in mice (Hu et al, 2020). With respect to BDNF, one line of evidence indicates that chronic stress increases transcript expression for BDNF in rats (Hammack et al, 2009), whereas defeat stress increased BDNF protein but not mRNA in BNST in the same species (Greenberg et al, 2014).…”

CRF neurons establish resilience via stress-history dependent BNST modulation

“…The BNST has been implicated in prosocial behaviors, and is a complex structure consisting of studies have implicated the overactivation of CRF neurons in the BNST as being pro-depressive and anxiogenic 31,39,46,47,49 , therefore, we were surprised to observe that BNSTov CRF neurons exhibited increased activity in resilient mice. Moreover, cell-type-specific activation of this CRF neuronal population yielded resiliency in mice.…”

“…CRF neurons of the BNST are a major output source of the oval BNST that are sensitive to chronic stressors 27,[45][46][47] . Thus, we hypothesized that chronic stress would alter BNSTov CRF neuronal activity coinciding with the divergence in resilient and susceptible behavioral phenotypes.…”

Early life exposure to high fructose diet induces metabolic dysregulation associated with sex-specific cognitive impairment in adolescent rats

“…Single-cell quantitative PCR: PCR was performed as previously described [26]. Cytoplasm was collected by a patch pipette under visual guidance by applying light suction.…”