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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 (BNSTALG) act to modulate anxiety in opposing ways. A history of chronic stress increases anxiety-like behavior with lasting electrophysiological effects on the BNSTALG. However, the opposing circuits within the BNSTALG 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 homogenoeus 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 BNSTALG. 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 BNSTALG circuit and represent a population of CRF neurons particularly sensitive to chronic stress.

SUBMITTER: Daniel SE

PROVIDER: S-EPMC6505688 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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

Daniel Sarah E SE Menigoz Aurélie A Guo Jidong J Ryan Steven J SJ Seth Shivani S Rainnie Donald G DG

Neuropharmacology 20190314

Distinct regions and cell types in the anterolateral group of the bed nucleus of the stria terminalis (BNSTALG) act to modulate anxiety in opposing ways. A history of chronic stress increases anxiety-like behavior with lasting electrophysiological effects on the BNSTALG. However, the opposing circuits within the BNSTALG suggest that stress may have differential effects on the individual cell types that comprise these circuits to shift the balance to favor anxioge ...[more]

PMID: 30878403

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Project description:The activity of neurons in the anterolateral cell group of the bed nucleus of the stria terminalis (BNST(ALG)) plays a critical role in anxiety- and stress-related behaviors. Histochemical studies have suggested that multiple distinct neuronal phenotypes exist in the BNST(ALG). Consistent with this observation, the physiological properties of BNST(ALG) neurons are also heterogeneous, and three distinct cell types can be defined (Types I-III) based primarily on their expression of four key membrane currents, namely I(h), I(A), I(T), and I(K(IR)). Significantly, all four channels are multimeric proteins and can comprise of more than one pore-forming α subunit. Hence, differential expression of α subunits may further diversify the neuronal population. However, nothing is known about the relative expression of these ion channel α subunits in BNST(ALG) neurons. We have addressed this lacuna by combining whole-cell patch-clamp recording together with single-cell reverse transcriptase polymerase chain reaction (scRT-PCR) to assess the mRNA transcript expression for each of the subunits for the four key ion channels in Type I-III neurons of the BNST(ALG.) Here, cytosolic mRNA from single neurons was probed for the expression of transcripts for each of the α subunits of I(h) (HCN1-HCN4), I(T) (Ca(v)3.1-Ca(v)3.3), I(A) (K(v)1.4, K(v)3.4, K(v)4.1-K(v) 4.3) and I(K(IR)) (Kir2.1-Kir2.4). An unbiased hierarchical cluster analysis followed by discriminant function analysis revealed that a positive correlation exists between the physiological and genetic phenotype of BNST(ALG) neurons. Thus, the analysis segregated BNST(ALG) neurons into 3 distinct groups, based on their α subunit mRNA expression profile, which positively correlated with our existing electrophysiological classification (Types I-III). Furthermore, analysis of mRNA transcript expression in Type I-Type III neurons suggested that, whereas Type I and III neurons appear to represent genetically homologous cell populations, Type II neurons may be further subdivided into three genetically distinct subgroups. These data not only validate our original classification scheme, but further refine the classification at the molecular level, and thus identifies novel targets for potential disruption and/or pharmacotherapeutic intervention in stress-related anxiety-like behaviors.

Dataset Information

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

Publications

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

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