Differential effects of static and dynamic inputs on neuronal excitability

The intrinsic excitability of neurons is known to be dynamically regulated by activity-dependent plasticity and homeostatic mechanisms. Such processes are commonly analyzed in the context of input-output functions that describe how neurons fire in response to constant levels of current. However, it is not well understood how changes of excitability as observed under static inputs translate to the function of the same neurons in their natural synaptic environment. Here we performed a computational study and hybrid experiments on rat bed nucleus of stria terminalis neurons to compare the two scenarios. The inward rectifying Kir current ( IKir) and the hyperpolarization-activated cation current ( Ih) were found to be considerably more effective in regulating the firing under synaptic inputs than under static stimuli. This prediction was experimentally confirmed by dynamic-clamp insertion of a synthetic inwardly rectifying Kir current into the biological neurons. At the same time, ionic currents that activate with depolarization were more effective regulating the firing under static inputs. When two intrinsic currents are concurrently altered such as those under homeostatic regulation, the effects in firing responses under static vs. dynamic inputs can be even more contrasting. Our results show that plastic or homeostatic changes of intrinsic membrane currents can shape the current step responses of neurons and their firing under synaptic inputs in a differential manner.

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Aging-Associated Changes to Intrinsic Neuronal Excitability in the Bed Nucleus of the Stria Terminalis Is Cell Type-Dependent

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2017.00424 ◽

2017 ◽

Vol 9 ◽

Cited By ~ 3

Author(s):

Hannah E. Smithers ◽

John R. Terry ◽

Jon T. Brown ◽

Andrew D. Randall

Keyword(s):

Neuronal Excitability ◽

Stria Terminalis ◽

Cell Type ◽

Bed Nucleus

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Inhibitory synaptic transmissions to the bed nucleus of the stria terminalis neurons projecting to the ventral tegmental area are enhanced in rats exposed to chronic mild stress

Molecular Brain ◽

10.1186/s13041-020-00684-4 ◽

2020 ◽

Vol 13 (1) ◽

Author(s):

Ryuto Hara ◽

Daiki Takahashi ◽

Tatsuhiro Takehara ◽

Taiju Amano ◽

Masabumi Minami

Keyword(s):

Chronic Pain ◽

Animal Models ◽

Ventral Tegmental Area ◽

Dopaminergic System ◽

Chronic Mild Stress ◽

Mild Stress ◽

Stria Terminalis ◽

Bed Nucleus ◽

Synaptic Inputs ◽

Neuroplastic Change

Abstract The comorbidities of depression and chronic pain have long been recognized in the clinic, and several preclinical studies have demonstrated depression-like behaviors in animal models of chronic pain. These findings suggest a common neuronal basis for depression and chronic pain. Recently, we reported that the mesolimbic dopaminergic system was tonically suppressed during chronic pain by enhanced inhibitory synaptic inputs to neurons projecting from the dorsolateral bed nucleus of the stria terminalis (dlBNST) to the ventral tegmental area (VTA), suggesting that tonic suppression of the mesolimbic dopaminergic system by this neuroplastic change may be involved in chronic pain-induced depression-like behaviors. In this study, we hypothesized that inhibitory synaptic inputs to VTA-projecting dlBNST neurons are also enhanced in animal models of depression, thereby suppressing the mesolimbic dopaminergic system. To test this hypothesis, we performed whole-cell patch-clamp electrophysiology using brain slices prepared from rats exposed to chronic mild stress (CMS), a widely used animal model of depression. The results showed a significant enhancement in the frequency of spontaneous inhibitory postsynaptic currents in VTA-projecting dlBNST neurons in the CMS group compared with the no stress group. The findings revealed enhanced inhibitory synaptic inputs to VTA-projecting dlBNST neurons in this rat model of depression, suggesting that this neuroplastic change is a neuronal mechanism common to depression and chronic pain that causes dysfunction of the mesolimbic dopaminergic system, thereby inducing depression-like behaviors.

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High-resolution and cell-type-specific photostimulation mapping shows weak excitatory vs. strong inhibitory inputs in the bed nucleus of the stria terminalis

Journal of Neurophysiology ◽

10.1152/jn.01148.2015 ◽

2016 ◽

Vol 115 (6) ◽

pp. 3204-3216 ◽

Cited By ~ 5

Author(s):

Xiangmin Xu ◽

Taruna Ikrar ◽

Yanjun Sun ◽

Rommel Santos ◽

Todd C. Holmes ◽

...

Keyword(s):

High Resolution ◽

Functional Organization ◽

Stria Terminalis ◽

Cell Type ◽

Experimental Conditions ◽

Bed Nucleus ◽

Local Circuit ◽

Synaptic Inputs ◽

Cell Type Specific ◽

Local Circuits

The bed nucleus of the stria terminalis (BNST) is a key component of the extended amygdala and has been implicated in anxiety and addiction. As individual neurons function within neural circuits, it is important to understand local microcircuits and larger network connections of identified neuronal types and understand how maladaptive changes in the BNST neural networks are induced by stress and drug abuse. However, due to limitations of classic anatomical and physiological methods, the local circuit organization of synaptic inputs to specific BNST neuron types is not well understood. In this study, we report on the application of high-resolution and cell-type-specific photostimulation methodology developed in our laboratory to local circuit mapping in the BNST. Under calibrated experimental conditions, laser photostimulation via glutamate uncaging or channelrhodopsin-2 photoactivation evokes spiking of BNST neurons perisomatically, without activating spikes from axons of passage or distal dendrites. Whole cell recordings, combined with spatially restricted photostimulation of presynaptic neurons at many different locations over a large region, allow high-resolution mapping of presynaptic input sources to single recorded neurons in the BNST. We constructed maps of synaptic inputs impinging onto corticotrophin-releasing hormone-expressing (CRH+) BNST neurons in the dorsolateral BNST and found that the CRH+ neurons receive predominant local inhibitory synaptic connections with very weak excitatory connections. Through cell-type-specific optogenetic stimulation mapping, we generated maps of somatostatin-expressing neuron-specific inhibitory inputs to BNST neurons. Taken together, the photostimulation-based techniques offer us powerful tools for determining the functional organization of local circuits of specific BNST neuron types.

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Glucagon-like peptide 1 receptor-mediated stimulation of a GABAergic projection from the bed nucleus of the stria terminalis to the hypothalamic paraventricular nucleus

10.1101/2021.03.04.433953 ◽

2021 ◽

Author(s):

Nadya Povysheva ◽

Huiyuan Zheng ◽

Linda Rinaman

Keyword(s):

Hpa Axis ◽

Paraventricular Nucleus ◽

Brain Slices ◽

Gabaergic Neurons ◽

Stria Terminalis ◽

Bed Nucleus ◽

Synaptic Inputs ◽

Bath Application ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

We previously reported that GABAergic neurons within the ventral anterior lateral bed nucleus of the stria terminalis (alBST) express glucagon-like peptide 1 receptor (GLP1R) in rats, and that virally-mediated <knock-down> of GLP1R expression in the alBST prolongs the hypothalamic-pituitary-adrenal axis response to acute stress. Given other evidence that a GABAergic projection pathway from ventral alBST serves to limit stress-induced activation of the HPA axis, we hypothesized that GLP1 signaling promotes activation of GABAergic ventral alBST neurons that project directly to the paraventricular nucleus of the hypothalamus (PVN). After PVN microinjection of fluorescent retrograde tracer followed by preparation of ex vivo rat brain slices, whole-cell patch clamp recordings were made in identified PVN-projecting neurons within the ventral alBST. Bath application of Exendin-4 (a specific GLP1R agonist) indirectly depolarized PVN-projecting neurons in the ventral alBST and adjacent hypothalamic parastrial nucleus (PS) via circuit-mediated effects that increased excitatory synaptic inputs and decreased inhibitory synaptic inputs to the PVN-projecting neurons; these effects were occluded by prior bath application of a GLP1R antagonist. Additional retrograde tracing experiments combined with in situ hybridization confirmed that PVN-projecting neurons within the ventral alBST/PS are GABAergic, and do not express GLP1R mRNA. Conversely, GLP1 mRNA is expressed by a subset of GABAergic neurons within the oval subnucleus of the dorsal alBST that project into the ventral alBST. Our novel findings reveal a potential GLP1R-mediated mechanism through which the alBST exerts inhibitory control over the endocrine HPA axis.

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Nociceptin/orphanin FQ and the regulation of neuronal excitability in the rat bed nucleus of the stria terminalis: Interaction with glucocorticoids

Stress ◽

10.3109/10253890.2010.491134 ◽

2010 ◽

Vol 13 (6) ◽

pp. 516-527 ◽

Cited By ~ 8

Author(s):

K. L. Dawe ◽

J. B. Wakerley ◽

A. J. Fulford

Keyword(s):

Neuronal Excitability ◽

Stria Terminalis ◽

Orphanin Fq ◽

Bed Nucleus

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Glycine receptor α3 and α2 subunits mediate tonic and exogenous agonist-induced currents in forebrain

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1703839114 ◽

2017 ◽

Vol 114 (34) ◽

pp. E7179-E7186 ◽

Cited By ~ 21

Author(s):

Lindsay M. McCracken ◽

Daniel C. Lowes ◽

Michael C. Salling ◽

Cyndel Carreau-Vollmer ◽

Naomi N. Odean ◽

...

Keyword(s):

Spinal Cord ◽

Prefrontal Cortex ◽

Neuronal Excitability ◽

Glycine Receptor ◽

Stria Terminalis ◽

Bed Nucleus ◽

Neuronal Inhibition ◽

Subunit Expression ◽

Inward Currents ◽

Α3 Subunit

Neuronal inhibition can occur via synaptic mechanisms or through tonic activation of extrasynaptic receptors. In spinal cord, glycine mediates synaptic inhibition through the activation of heteromeric glycine receptors (GlyRs) composed primarily of α1 and β subunits. Inhibitory GlyRs are also found throughout the brain, where GlyR α2 and α3 subunit expression exceeds that of α1, particularly in forebrain structures, and coassembly of these α subunits with the β subunit appears to occur to a lesser extent than in spinal cord. Here, we analyzed GlyR currents in several regions of the adolescent mouse forebrain (striatum, prefrontal cortex, hippocampus, amygdala, and bed nucleus of the stria terminalis). Our results show ubiquitous expression of GlyRs that mediate large-amplitude currents in response to exogenously applied glycine in these forebrain structures. Additionally, tonic inward currents were also detected, but only in the striatum, hippocampus, and prefrontal cortex (PFC). These tonic currents were sensitive to both strychnine and picrotoxin, indicating that they are mediated by extrasynaptic homomeric GlyRs. Recordings from mice deficient in the GlyR α3 subunit (Glra3−/−) revealed a lack of tonic GlyR currents in the striatum and the PFC. In Glra2−/Y animals, GlyR tonic currents were preserved; however, the amplitudes of current responses to exogenous glycine were significantly reduced. We conclude that functional α2 and α3 GlyRs are present in various regions of the forebrain and that α3 GlyRs specifically participate in tonic inhibition in the striatum and PFC. Our findings suggest roles for glycine in regulating neuronal excitability in the forebrain.

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Corticotropin-Releasing Hormone Signaling in the Oval Bed Nucleus of the Stria Terminalis Mediates Chronic Stress-Induced Negative Valence Behaviors Associated with Anxiety

10.1101/572966 ◽

2019 ◽

Author(s):

Pu Hu ◽

Isabella Maita ◽

Christopher Kwok ◽

Edward Gu ◽

Mark Gergues ◽

...

Keyword(s):

Chronic Stress ◽

Neuronal Excitability ◽

Tyrosine Phosphatase ◽

Molecular Signature ◽

Mild Stress ◽

Stria Terminalis ◽

Corticotropin Releasing Hormone ◽

Bed Nucleus ◽

Releasing Hormone ◽

Negative Valence

AbstractThe bed nucleus of stria terminalis (BNST) is a forebrain region highly sensitive to stress that expresses corticotropin-releasing hormone (CRH) neuropeptide at high levels and regulates negative valence behaviors associated with anxiety. However, how chronic stress modulates CRH signaling and neuronal activity in BNST remains unknown. We subjected C57BL6/J mice to a 6-week chronic variable mild stress (CVMS) paradigm and investigated the effects on behavior, BNST cellular neurophysiology, and BNST CRH signaling. We also utilized pharmacological infusions and optogenetics to decipher and mimic the effects of CVMS on BNST cellular neurophysiology and behavior. CVMS elevated plasma corticosterone levels, induced negative valence behaviors associated with anxiety, diminished M-currents (voltage-gated K+currents that stabilize membrane potential and regulate neuronal excitability), and increased mEPSC amplitude in ovBNST. Additionally, the number of c-fos+, CRH+, and CRH activator pituitary adenylate cyclase-activating polypeptide (PACAP)+cells were increased while CRH inhibitor striatal-enriched protein tyrosine phosphatase (STEP)+cells were decreased in ovBNST. These expression data were confirmed with qPCR. CVMS also activated PKA in BNST and the electrophysiological and behavioral effects of CVMS were reversed by ovBNST infusion of the PKA-selective antagonist H89. Moreover, optogenetic activation of ovBNST directly induced negative valence behaviors associated with anxiety, mimicking the effects of CVMS. CVMS mediates effects on negative valence behaviors associated with anxiety by activating CRH signaling components and cellular excitability in ovBNST Our findings decipher an important CRH-associated stress molecular signature in BNST and advance our understanding of the neural circuitry underlying stress-induced disorders.

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