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We previously reported that enhanced corticotropin-releasing factor (CRF) signaling in the bed nucleus of the stria terminalis (BNST) caused the aversive responses during acute pain and suppressed the brain reward system during chronic pain. However, it remains to be examined whether chronic pain alters the excitability of CRF neurons in the BNST. In this study we investigated the chronic pain-induced changes in excitability of CRF-expressing neurons in the oval part of the BNST (ovBNST CRF neurons) by whole-cell patch-clamp electrophysiology. CRF-Cre; Ai14 mice were used to visualize CRF neurons by tdTomato. Electrophysiological recordings from brain slices prepared from a mouse model of neuropathic pain revealed that rheobase and firing threshold were significantly decreased in the chronic pain group compared with the sham-operated control group. Firing rate of the chronic pain group was higher than that of the control group. These data indicate that chronic pain elevated neuronal excitability of ovBNST CRF neurons., (© 2024. The Author(s).)

The comorbidity of chronic pain and mental dysfunctions such as depression and anxiety disorders has long been recognized, but the underlying mechanisms remain poorly understood. Here, using a mouse model of neuropathic pain, we demonstrated neuronal plasticity in the bed nucleus of the stria terminalis (BNST), which plays a critical role in chronic pain-induced maladaptive anxiety. Electrophysiology demonstrated that chronic pain increased inhibitory inputs to lateral hypothalamus (LH)-projecting BNST neurons. Chemogenetic manipulation revealed that sustained suppression of LH-projecting BNST neurons played a crucial role in chronic pain-induced anxiety. Furthermore, using a molecular genetic approach, we demonstrated that chronic pain elevated the excitability of a specific subpopulation of BNST neurons, which express cocaine- and amphetamine-regulated transcript (CART). The elevated excitability of CART-positive neurons caused the increased inhibitory inputs to LH-projecting BNST neurons, thereby inducing anxiety-like behavior. These findings shed light on how chronic pain induces psychiatric disorders, characterized by maladaptive anxiety.

Gonadal steroid hormone influences behavioral choice of adult animals toward pups, parental or aggressive. We previously reported that long-term administration of 17β-estradiol (E2) to male mice during sexual maturation induces aggressive behavior toward conspecific pups, which is called "infanticide," and significantly enhanced excitatory synaptic transmission in the rhomboid nucleus of bed nucleus of the stria terminalis (BSTrh), which is an important brain region for infanticide. However, it is unclear how estrogen receptor-dependent signaling after sexual maturity regulates neural circuits including the BSTrh. Here we revealed that E2 administration to gonadectomized mice in adulthood elicited infanticidal behavior and enhanced excitatory synaptic transmission in the BSTrh by increasing the probability of glutamate release from the presynaptic terminalis. Next, we performed whole-brain mapping of E2-sensitive brain regions projecting to the BSTrh and found that amygdalohippocampal area (AHi) neurons that project to the BSTrh densely express estrogen receptor 1 (Esr1). Moreover, E2 treatment enhanced synaptic connectivity in the AHi-BSTrh pathway. Together, these results suggest that reinforcement of excitatory inputs from AHi neurons into the BSTrh by estrogen receptor-dependent signaling may contribute to the expression of infanticide., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

We examined the effects of neurotensin (NTS) on the excitability of type II neurons in the rat dorsolateral bed nucleus of the stria terminalis (dlBNST) using whole-cell patch-clamp electrophysiology. Bath-application of NTS depolarized type II dlBNST neurons. Analyses of the steady-state I-V relationships implied that the depolarizing effect of NTS is due to potassium conductance blocking. The depolarizing effect of NTS was abolished in the presence of a PLC inhibitor, but not affected by a protein kinase C inhibitor. In the presence of a CaMKII inhibitor, NTS showed depolarizing effects via the increase in non-selective cation conductance in addition to the decrease in potassium conductance. Unexpectedly, in the presence of a PKA inhibitor, NTS hyperpolarized type II dlBNST neurons. These results reveal that diverse signaling pathways mediate the effects of NTS on the excitability of type II dlBNST neurons. The elevation of intracellular Ca 2+ levels via the inositol phosphate-mediated signaling activates both Ca 2+ -dependent adenylate cyclase (AC) and CaMKII. Activation of the AC-cAMP-PKA pathway exerts depolarizing effects on type II dlBNST neurons by decreasing potassium conductance and increasing non-selective cation conductance, whereas activation of the CaMKII pathway exerts hyperpolarizing effects on dlBNST neurons by decreasing non-selective cation conductance., Competing Interests: Declaration of competing interest No competing interest., (Copyright © 2021 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

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.

We recently showed that the mesolimbic dopaminergic system was tonically suppressed during chronic pain by enhanced corticotropin releasing factor (CRF) signaling within the dorsolateral bed nucleus of the stria terminalis (dlBNST), and that inhibition of intra-dlBNST CRF signaling restored the mesolimbic dopaminergic system function. Specifically, bilateral intra-dlBNST injections of the CRF type 1 receptor antagonist NBI27914 increased intra-nucleus accumbens dopamine release and induced reward-related behaviors in rats with chronic pain. Here, we used a conditioned place preference (CPP) test to explore whether intra-dlBNST injections of neuropeptide Y (NPY) restored the mesolimbic reward system function in chronic pain rats, because we previously showed that NPY had an effect opposite to that of CRF in dlBNST neurons. Specifically, CRF depolarized type II dlBNST neurons whereas NPY hyperpolarized them. However, unexpectedly, intra-dlBNST NPY injections had no effect on CPP test outcomes. Then, we compared the effects of NPY on the membrane potentials of type II dlBNST neurons of sham-operated control rats and those of chronic pain animals. Whole-cell patch-clamp electrophysiology revealed that NPY hyperpolarized type II dlBNST neurons in the sham-operated group. By contrast, in the chronic pain group, NPY did not hyperpolarize, but rather depolarized, type II dlBNST neurons. These results indicate that NPY no longer hyperpolarizes type II dlBNST neurons in rats with chronic pain, therefore it does not reverse the excitatory effects of CRF. This may be why intra-dlBNST injections of NPY into chronic pain rats did not exhibit a rewarding effect in the CPP test, whereas intra-dlBNST injections of NBI27914 did. This is the first study to demonstrate a chronic pain-induced neuroplastic change in NPY signaling in the dlBNST. Such a change may be involved in the dysfunction of the mesolimbic reward system under the chronic pain condition., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Although dysfunction of the mesolimbic dopaminergic system has been implicated in chronic pain, the underlying mechanisms remain to be elucidated. We hypothesized that increased inhibitory inputs to the neuronal pathway from the dorsolateral bed nucleus of the stria terminalis (dlBNST) to the ventral tegmental area (VTA) during chronic pain may induce tonic suppression of the mesolimbic dopaminergic system. To test this hypothesis, male Sprague Dawley rats were subjected to spinal nerve ligation to induce neuropathic pain and then spontaneous IPSCs (sIPSCs) were measured in this neuronal pathway. Whole-cell patch-clamp electrophysiology of brain slices containing the dlBNST revealed that the frequency of sIPSCs significantly increased in VTA-projecting dlBNST neurons 4 weeks after surgery. Next, the role of corticotropin-releasing factor (CRF) signaling within the dlBNST in the increased sIPSCs was examined. CRF increased the frequency of sIPSCs in VTA-projecting dlBNST neurons in sham-operated controls, but not in chronic pain rats. By contrast, NBI27914, a CRF type 1 receptor antagonist, decreased the frequency of sIPSCs in VTA-projecting dlBNST neurons in the chronic pain rats, but not in the control animals. In addition, histological analyses revealed the increased expression of CRF mRNA in the dlBNST. Finally, bilateral injections of NBI27914 into the dlBNST of chronic pain rats activated mesolimbic dopaminergic neurons and induced conditioned place preference. Together, these results suggest that the mesolimbic dopaminergic system is tonically suppressed during chronic pain by enhanced CRF signaling within the dlBNST via increased inhibitory inputs to VTA-projecting dlBNST neurons. SIGNIFICANCE STATEMENT The comorbidity of chronic pain and depression has long been recognized. Although dysfunction of the mesolimbic dopaminergic system has been implicated in both chronic pain and depression, the underlying mechanisms remain to be elucidated. Here, we show that the inhibitory inputs to the neuronal pathway from the dorsolateral bed nucleus of the stria terminalis (dlBNST) to the ventral tegmental area increase during chronic pain. This neuroplastic change is mediated by enhanced corticotropin-releasing factor signaling within the dlBNST that leads to tonic suppression of the mesolimbic dopaminergic system, which may be involved in the depressive mood and anhedonia under the chronic pain condition., (Copyright © 2019 the authors.)

Sexually immature male mice exhibit parenting behavior toward unfamiliar pups; however, the percentage of males that engage in infanticidal behavior gradually increases with age. We previously reported that excitatory synaptic transmission of the rhomboid nucleus of the bed nucleus of the stria terminalis (BSTrh), a brain region implicated in infanticidal behavior, is reinforced during pubertal development. However, it remains unclear how gonadal steroid hormones mediate this behavioral transition and neural plastic change during pubertal development. Here we revealed that administration of either 17β-estradiol (E2) or 5α-dihydrotestosterone (DHT) to gonadectomized mice during pubertal development induced infanticidal behavior in adulthood (about 7 weeks old). Next, we performed whole-cell patch clamp recording in the BSTrh to study the effect of gonadal steroid hormones on neural synaptic transmission. We found that E2 but not DHT administration during pubertal development considerably enhanced excitatory synaptic transmission in the BSTrh by increasing the probability of excitatory neurotransmitter release from the presynaptic terminalis. These data suggest that reinforcement of excitatory synaptic transmission by estrogen-receptor-dependent signaling in the BSTrh during puberty may contribute to the development of infanticidal behavior., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The bed nucleus of the stria terminalis (BNST) and the central amygdala (CeA) comprise a forebrain unit that has been described as the "extended amygdala". These two nuclei send dense projections to each other and have been implicated in the regulation of negative emotional states, including anxiety and fear. The present study employed an optogenetic technique to examine whether stimulation of CeA-projecting dorsolateral BNST (dlBNST) neuron terminals would influence anxiety-like behaviors in male Sprague-Dawley rats. Photostimulation of CeA-projecting dlBNST neuron terminals produced anxiogenic effects in an elevated plus maze test. This finding is inconsistent with previous reports showing that optogenetic stimulation of BNST neurons projecting to the lateral hypothalamus (LH) and ventral tegmental area (VTA) produces anxiolytic rather than anxiogenic effects. To address this issue, electrophysiological analyses were conducted to characterize dlBNST neurons projecting to the CeA, LH, and VTA. dlBNST neurons can be electrophysiologically classified into three distinct cell types (types I-III) according to their responses to depolarizing and hyperpolarizing current injections. Whole-cell patch-clamp recordings revealed that more than 60% of the CeA-projecting dlBNST neurons were type II, whereas approximately 80% of the LH- and VTA-projecting dlBNST neurons were type III. These electrophysiological results will help elucidate the mechanisms underlying the heterogeneity of BNST neurons during the regulation of anxiety-like behaviors., (© 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Pain consists of sensory and affective components. Although the neuronal mechanisms underlying the sensory component of pain have been studied extensively, those underlying its affective component are only beginning to be elucidated. Previously, we showed the pivotal role of the ventral part of the bed nucleus of the stria terminalis (vBNST) in the negative affective component of pain. Here, we examined the role of glutamate-nitric oxide (NO) signaling in the affective component of pain in rats using a conditioned place aversion (CPA) test. Intra-vBNST injection of either CNQX (an AMPA receptor antagonist) or MK-801 (an NMDA receptor antagonist) dose-dependently attenuated intraplantar formalin-induced CPA (F-CPA) without reducing nociceptive behaviors. In vivo microdialysis showed that extracellular oxidative NO metabolites (NOx) levels were significantly increased by intraplantar formalin injection. Intra-vBNST injection of NPLA (a selective neuronal NO synthase (nNOS) inhibitor), c-PTIO (a NO scavenger), or ZL006 (a postsynaptic density-95 (PSD-95)-nNOS interaction inhibitor) dose-dependently suppressed F-CPA without attenuating nociceptive behaviors. Intra-vBNST injection of NOR3 (a NO donor) produced CPA in a dose-dependent manner in the absence of noxious stimulation. Furthermore, whole-cell patch-clamp electrophysiology in the vBNST slices revealed that NOR3 induced depolarization of hyperpolarization-activated cation current (I h )-positive vBNST neurons, which was blocked by the NO scavenger. These results suggest that activation of glutamatergic transmission and subsequent nNOS-derived NO production within the vBNST mediate the negative affective component of pain and that NO-evoked excitation of I h -positive vBNST neurons may be among the cellular mechanisms underlying pain-induced aversion., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Sexually naïve male C57BL/6 mice aggressively bite unfamiliar pups. This behavior, called infanticide, is considered an adaptive reproductive strategy of males of polygamous species. We recently found that the rhomboid nucleus of the bed nucleus of the stria terminalis (BSTrh) is activated during infanticide and that the bilateral excitotoxic lesions of BSTrh suppress infanticidal behavior. Here we show that 3-week-old male C57BL/6 mice rarely engaged in infanticide and instead, provided parental care toward unfamiliar pups, consistent with observations in rats and other rodent species. This inhibition of infanticide at the periweaning period is functional because the next litter will be born at approximately the time of weaning of the previous litter through maternal postpartum ovulation. However, the mechanism of this age-dependent behavioral change is unknown. Therefore, we performed whole-cell patch clamp recordings of BSTrh and compared evoked neurotransmission in response to the stimulation of the stria terminalis of adult and 3-week-old male mice. Although we were unable to detect a significant difference in the amplitudes of inhibitory neurotransmission, the amplitudes and the paired-pulse ratio of evoked excitatory postsynaptic currents differed between adult and 3-week-old mice. These data suggest that maturation of the synaptic terminal in BSTrh that occurred later than 3 weeks after birth may mediate by the adaptive change from parental to infanticidal behavior in male mice., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Pain is a complex experience involving sensory and affective components. Although the neuronal mechanisms underlying the sensory component of pain have been extensively studied, those underlying its affective component have yet to be elucidated. Recently, we reported that corticotrophin-releasing factor (CRF)-induced depolarization in type II neurons within the dorsolateral bed nucleus of the stria terminalis (dlBNST) is critical for pain-induced aversive responses in rats. However, the intracellular signaling underlying the excitatory effects of CRF and the contribution of such signaling to the induction of pain-induced aversion remain unclear. In the present study, we addressed these issues by conducting whole-cell patch-clamp recordings in rat brain slices and by undertaking behavioral pharmacological analyses. Intracellular perfusion of protein kinase A (PKA) inhibitor Rp-cyclic adenosine monophosphorothioate (Rp-cAMPS) or KT5720 suppressed the excitatory effects of CRF in type II dlBNST neurons, and bath application of Rp-cAMPS also suppressed it. In addition, bath application of forskolin, an adenylate cyclase (AC) activator, mimicked the effects of CRF, and pretreatment with forskolin diminished the excitatory effects of CRF. Furthermore, a conditioned place aversion (CPA) test showed that co-administration of Rp-cAMPS with CRF into the dlBNST suppressed CRF-induced CPA. Intra-dlBNST injection of Rp-cAMPS also suppressed pain-induced CPA. These results suggest that CRF increases excitability of type II dlBNST neurons through activation of the AC-cAMP-PKA pathway, thereby causing pain-induced aversive responses. The present findings shed light on the neuronal mechanisms underlying the negative affective component of pain and may provide therapeutic targets for treating intractable pain accompanied by psychological factors., (© 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)