Activation of Lateral Parabrachial Nucleus (LPBn) PACAP-Expressing Projection Neurons to the Bed Nucleus of the Stria Terminalis (BNST) Enhances Anxiety-like Behavior

2021 ◽  
Author(s):  
Melissa N. Boucher ◽  
Mahafuza Aktar ◽  
Karen M. Braas ◽  
Victor May ◽  
Sayamwong E. Hammack
Keyword(s):  
Parabrachial Nucleus ◽  
Projection Neurons ◽  
Stria Terminalis ◽  
Bed Nucleus ◽  
Lateral Parabrachial Nucleus

scholarly journals Divergent neural pathways emanating from the lateral parabrachial nucleus mediate distinct components of the pain response

2019 ◽  
Author(s):  
Michael C. Chiang ◽  
Eileen K. Nguyen ◽  
Andrew E. Papale ◽  
Sarah E. Ross
Keyword(s):  
Ventromedial Hypothalamus ◽  
Parabrachial Nucleus ◽  
Projection Neurons ◽  
Pain Response ◽  
Neural Pathways ◽  
Bed Nucleus ◽  
Lateral Parabrachial Nucleus ◽  
Efferent Projections ◽  
Efferent Neurons ◽  
Nociceptive Input

ABSTRACTThe lateral parabrachial nucleus (lPBN) is a major target of spinal projection neurons conveying nociceptive input into supraspinal structures. However, the functional role of distinct lPBN efferents for diverse nocifensive responses have remained largely uncharacterized. Here, we show that two populations of efferent neurons from different regions of the lPBN collateralize to distinct targets. Activation of efferent projections to the ventromedial hypothalamus (VMH) or lateral periaqueductal gray (lPAG) drive escape behaviors, whereas the activation of lPBN efferents to the bed nucleus stria terminalis (BNST) or central amygdala (CEA) generates an aversive memory. Finally, we provide evidence that dynorphin expressing neurons span cytoarchitecturally distinct domains of the lPBN to coordinate these distinct aspects of the nocifensive response.HIGHLIGHTSSpatially segregated neurons in the lPBN collateralize to distinct targets.Distinct output pathways give rise to separate aspects of the pain response.Dynorphin neurons within the lPBN convey noxious information across subdivisions.eTOC BLURBChiang et al. reveal that neurons in spatially segregated regions of the lateral parabrachial nucleus collateralize to distinct targets, and that activation of distinct efferents gives rise to separate components of the nocifensive response.

scholarly journals Enhanced synaptic transmission in the extended amygdala and altered excitability in an extended amygdala to brainstem circuit in a Dravet syndrome mouse model

2020 ◽  
Author(s):  
Wen Wei Yan ◽  
Maya Xia ◽  
Alyssa Levitt ◽  
Nicole Hawkins ◽  
Jennifer Kearney ◽  
...  
Keyword(s):  
Sudden Death ◽  
Early Onset ◽  
Dravet Syndrome ◽  
Parabrachial Nucleus ◽  
Projection Neurons ◽  
Stria Terminalis ◽  
Respiratory Dysfunction ◽  
Bed Nucleus ◽  
Extended Amygdala ◽  
Spontaneous Seizures

ABSTRACTObjectiveDravet syndrome (DS) is a severe, early-onset epilepsy with an increased incidence of sudden death. Evidence of interictal breathing deficits in DS suggest that alterations in subcortical projections to brainstem nuclei may exist, which might be driving comorbidities in DS. The aim of this study was to determine if a subcortical structure, the bed nucleus of the stria terminalis (BNST) in the extended amygdala, is activated by seizures, exhibits changes in excitability, and expresses any alterations in neurons projecting to a brainstem nucleus associated with respiration, stress response and homeostasis.MethodsExperiments were conducted using F1 mice generated by breeding 129.Scn1a+/- mice with wildtype C57BL/6J mice. Immunohistochemistry was performed to quantify neuronal c-fos activation in DS mice after observed spontaneous seizures. Whole cell patch clamp and current clamp electrophysiology recordings were conducted to evaluate changes in intrinsic and synaptic excitability in the BNST.ResultsSpontaneous seizures in DS mice significantly enhanced neuronal c-fos expression in the BNST. Further, the BNST had altered AMPA/NMDA postsynaptic receptor composition and showed changes in spontaneous neurotransmission, with greater excitation and decreased inhibition. BNST to parabrachial nucleus (PBN) projection neurons exhibited intrinsic excitability in wildtype mice, while these projection neurons were hypoexcitable in DS mice.SignificanceThe findings suggest that there is altered excitability in neurons of the BNST, including BNST to PBN projection neurons, in DS mice. These alterations could potentially be driving comorbid aspects of DS outside of seizures, including respiratory dysfunction and sudden death.SIGNIFICANCE STATEMENTDravet syndrome (DS) is an early-onset epilepsy with an increased risk of sudden death. We determined that there are alterations in a subcortical nucleus, the bed nucleus of the stria terminalis (BNST) of the extended amygdala, in a murine DS model. The BNST is involved in stress, anxiety, feeding, and respiratory function. We found enhanced activation in the BNST after seizures and alterations in basal synaptic neurotransmission–with enhanced spontaneous excitatory and decreased spontaneous inhibitory postsynaptic events. Evaluating those neurons that project to the parabrachial nucleus (PBN), a nucleus with multiple homeostatic roles, we found them to be hypoexcitable in DS. Alterations in BNST to brainstem projections could be implicated in comorbid aspects of DS, including respiratory dysfunction and sudden death.

scholarly journals Forebrain neurons that project to the gustatory parabrachial nucleus in rat lack glutamic acid decarboxylase

2008 ◽  
Vol 294 (1) ◽  
pp. R52-R57 ◽  
Author(s):  
Shalini Saggu ◽  
Robert F. Lundy
Keyword(s):  
Glutamic Acid ◽  
Glutamic Acid Decarboxylase ◽  
Input Resistance ◽  
Central Nucleus ◽  
Parabrachial Nucleus ◽  
Acid Decarboxylase ◽  
Inhibitory Influence ◽  
Stria Terminalis ◽  
Bed Nucleus ◽  
Forebrain Neurons

Evidence suggests that GABA might mediate the inhibitory influence of centrifugal inputs on taste-evoked responses in the parabrachial nucleus (PBN). Previous studies show that activation of the gustatory cortex (GC), bed nucleus of the stria terminalis (BNST), central nucleus of the amygdala (CeA), and lateral hypothalamus (LH) inhibits PBN taste responses, GABAergic neurons are present in these forebrain regions, and GABA reduces the input resistance of PBN neurons. The present study investigated the expression of glutamic acid decarboxylase immunoreactivity (GAD_67 ir) in GC, BNST, CeA, and LH neurons that project to the PBN in rats. After anesthesia (50 mg/kg ip Nembutal), injections of the retrograde tracer Fluorogold (FG) were made in the physiologically defined gustatory PBN. Brain tissue containing the above forebrain structures was processed and examined for FG and GAD_67 ir. Similar to previous studies, each forebrain site contained retrogradely labeled neurons. Our results suggest further that the major source of input to the PBN taste region is the CeA (608 total cells) followed by GC (257 cells), LH (106 cells), and BNST (92 cells). This suggests a differential contribution to centrifugal control of PBN taste processing. We further show that despite the presence of GAD_67 neurons in each forebrain area, colocalization was extremely rare, occurring only in 3 out of 1,063 FG-labeled cells. If we assume that the influence of centrifugal input is mediated by direct projections to the gustatory region of the PBN, then GABAergic forebrain neurons apparently are not part of this descending pathway.

scholarly journals Oxytocin selectively excites interneurons and inhibits output neurons of the bed nucleus of the stria terminalis (BNST)

2020 ◽  
Author(s):  
Walter Francesconi ◽  
Fulvia Berton ◽  
Valentina Olivera-Pasilio ◽  
Joanna Dabrowska
Keyword(s):  
Male Rats ◽  
Membrane Properties ◽  
Projection Neurons ◽  
Type I ◽  
Stria Terminalis ◽  
Type Ii ◽  
Spontaneous Firing ◽  
Bed Nucleus ◽  
Type Iii ◽  
Output Neurons

AbstractThe dorsolateral bed nucleus of the stria terminalis (BNSTDL) has high expression of oxytocin receptors, but their role in the modulation of BNSTDL activity remains elusive. BNSTDL contains GABA-ergic neurons classified based on intrinsic membrane properties into three types. Using in vitro patch-clamp and cell-attached recordings in male rats, we demonstrate that oxytocin excites and increases spontaneous firing of Type I, putative BNSTDL interneurons. As a consequence, oxytocin increases the frequency of spontaneous inhibitory post-synaptic currents (sIPSCs) (tetrodotoxin-sensitive) and reduces spontaneous firing of Type II neurons. In contrast, in Type III neurons, oxytocin reduces the amplitude of both sIPSCs and evoked IPSCs, suggesting a direct postsynaptic inhibitory effect. As Type II and Type III are the BNSTDL projection neurons, we present a model of fine-tuned modulation by oxytocin, which selectively excites Type I BNSTDL interneurons and inhibits Type II and Type III output neurons, via an indirect and direct mechanism, respectively.

scholarly journals Disruption of synaptic transmission in the Bed Nucleus of the Stria Terminalis reduces seizure-induced death in DBA/1 mice and alters brainstem E/I balance

2021 ◽  
Author(s):  
Maya Xia ◽  
Benjamin Owen ◽  
Jeremy Chiang ◽  
Alyssa Levitt ◽  
Wen Wei Yan ◽  
...  
Keyword(s):  
Ventilatory Response ◽  
Respiratory Arrest ◽  
Audiogenic Seizures ◽  
Stria Terminalis ◽  
Hypoxic Ventilatory Response ◽  
Unexpected Death ◽  
Bed Nucleus ◽  
Tetanus Neurotoxin ◽  
Lateral Parabrachial Nucleus ◽  
High Incidence

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in refractory epilepsy patients. Accumulating evidence from recent human studies and animal models suggests that seizure-related respiratory arrest may be important for initiating cardiorespiratory arrest and death. Prior evidence suggests that apnea onset can coincide with seizure spread to the amygdala and that stimulation of the amygdala can reliably induce apneas in epilepsy patients, potentially implicating amygdalar regions in seizure-related respiratory arrest and subsequent postictal hypoventilation and cardiorespiratory death. This study aimed to determine if an extended amygdalar structure, the dorsal bed nucleus of the stria terminalis (dBNST), is involved in seizure-induced respiratory arrest (S-IRA) and death using DBA/1 mice, a mouse strain which has audiogenic seizures and a high incidence of postictal respiratory arrest and death. The presence of S-IRA significantly increased c-Fos expression in the dBNST of DBA/1 mice. Furthermore, disruption of synaptic output from the dBNST via viral-induced tetanus neurotoxin significantly improved survival following S-IRA in DBA/1 mice without affecting baseline breathing or hypercapnic and hypoxic ventilatory response. This disruption in the dBNST resulted in changes to the balance of excitatory/inhibitory synaptic events in the downstream brainstem regions of the lateral parabrachial nucleus (PBN) and the periaqueductal gray (PAG). These findings suggest that the dBNST is a potential subcortical forebrain site necessary for the mediation of seizure-induced respiratory arrest, potentially through its outputs to brainstem respiratory regions.

scholarly journals A spinoparabrachial circuit defined by Tacr1 expression drives pain

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Arnab Barik ◽  
Anupama Sathyamurthy ◽  
James H Thompson ◽  
Mathew Seltzer ◽  
Ariel J Levine ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Negative Emotions ◽  
Parabrachial Nucleus ◽  
Projection Neurons ◽  
Spinal Neurons ◽  
Lateral Parabrachial Nucleus ◽  
Ongoing Pain ◽  
And Behaviors ◽  
Noxious Stimuli ◽  
Pain Responses

Painful stimuli evoke a mixture of sensations, negative emotions and behaviors. These myriad effects are thought to be produced by parallel ascending circuits working in combination. Here we describe a pathway from spinal cord to brain for ongoing pain. Activation of a subset of spinal neurons expressing Tacr1 evokes a full repertoire of somatotopically-directed pain-related behaviors in the absence of noxious input. Tacr1 projection neurons (expressing NKR1) target a tiny cluster of neurons in the superior lateral parabrachial nucleus (PBN-SL). We showed that these neurons, which also express Tacr1 (PBN-SLTacr1), are responsive to sustained but not acute noxious stimuli. Activation of PBN-SLTacr1 neurons alone did not trigger pain responses but instead served to dramatically heighten nocifensive behaviors and suppress itch. Remarkably, mice with silenced PBN-SLTacr1 neurons ignored long-lasting noxious stimuli. Together, these data reveal new details about this spinoparabrachial pathway and its key role in the sensation of ongoing pain.

scholarly journals Functional identification of a neurocircuit regulating blood glucose

2016 ◽  
Vol 113 (14) ◽  
pp. E2073-E2082 ◽  
Author(s):  
Thomas H. Meek ◽  
Jarrell T. Nelson ◽  
Miles E. Matsen ◽  
Mauricio D. Dorfman ◽  
Stephan J. Guyenet ◽  
...  
Keyword(s):  
Brain Area ◽  
Physiological Role ◽  
Selective Inhibition ◽  
Stria Terminalis ◽  
Synaptic Connections ◽  
Functional Identification ◽  
Steroidogenic Factor 1 ◽  
Bed Nucleus ◽  
Lateral Parabrachial Nucleus ◽  
Specific Subset

Previous studies implicate the hypothalamic ventromedial nucleus (VMN) in glycemic control. Here, we report that selective inhibition of the subset of VMN neurons that express the transcription factor steroidogenic-factor 1 (VMNSF1 neurons) blocks recovery from insulin-induced hypoglycemia whereas, conversely, activation of VMNSF1 neurons causes diabetes-range hyperglycemia. Moreover, this hyperglycemic response is reproduced by selective activation of VMNSF1 fibers projecting to the anterior bed nucleus of the stria terminalis (aBNST), but not to other brain areas innervated by VMNSF1 neurons. We also report that neurons in the lateral parabrachial nucleus (LPBN), a brain area that is also implicated in the response to hypoglycemia, make synaptic connections with the specific subset of glucoregulatory VMNSF1 neurons that project to the aBNST. These results collectively establish a physiological role in glucose homeostasis for VMNSF1 neurons and suggest that these neurons are part of an ascending glucoregulatory LPBN→VMNSF1→aBNST neurocircuit.

scholarly journals Expression of Fos during sham sucrose intake in rats with central gustatory lesions

2008 ◽  
Vol 295 (3) ◽  
pp. R751-R763 ◽  
Author(s):  
Suriyaphun S. Mungarndee ◽  
Robert F. Lundy ◽  
Ralph Norgren
Keyword(s):  
Central Nucleus ◽  
Parabrachial Nucleus ◽  
Stria Terminalis ◽  
Sucrose Intake ◽  
Solitary Tract ◽  
Final Test ◽  
Taste System ◽  
Bed Nucleus ◽  
Thalamic Lesions ◽  
Gustatory Neurons

For humans and rodents, ingesting sucrose is rewarding. This experiment tested the prediction that the neural activity produced by sapid sucrose reaches reward systems via projections from the pons through the limbic system. Gastric cannulas drained ingested fluid before absorption. For 10 days, the rats alternated an hour of this sham ingestion between sucrose and water. On the final test day, half of them sham drank water and the other half 0.6 M sucrose. Thirty minutes later, the rats were killed and their brains immunohistochemically stained for Fos. The groups consisted of controls and rats with excitotoxic lesions in the gustatory thalamus (TTA), the medial (gustatory) parabrachial nucleus (PBN), or the lateral (visceral afferent) parabrachial nucleus. In controls, compared with water, sham ingesting sucrose produced significantly more Fos-positive neurons in the nucleus of the solitary tract, PBN, TTA, and gustatory cortex (GC). In the ventral forebrain, sucrose sham licking increased Fos in the bed nucleus of the stria terminalis, central nucleus of amygdala, and the shell of nucleus accumbens. Thalamic lesions blocked the sucrose effect in GC but not in the ventral forebrain. After lateral PBN lesions, the Fos distributions produced by distilled H2O or sucrose intake did not differ from controls. Bilateral medial PBN damage, however, eliminated the sucrose-induced Fos increase not only in the TTA and GC but also in the ventral forebrain. Thus ventral forebrain areas associated with affective responses appear to be activated directly by PBN gustatory neurons rather than via the thalamocortical taste system.

scholarly journals A spinoparabrachial circuit defined by Tacr1 expression drives pain

2020 ◽  
Author(s):  
Arnab Barik ◽  
Anupama Sathyamurthy ◽  
James Thompson ◽  
Mathew Seltzer ◽  
Ariel Levine ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Negative Emotions ◽  
Parabrachial Nucleus ◽  
Projection Neurons ◽  
Coping Behaviors ◽  
Lateral Parabrachial Nucleus ◽  
Spinal Projection ◽  
Ongoing Pain ◽  
And Behaviors ◽  
Noxious Stimuli

AbstractPainful stimuli evoke a mixture of sensations, negative emotions and behaviors. These myriad effects are thought to be produced by parallel ascending circuits working in combination. Here we describe a pathway from spinal cord to brain for ongoing pain. Activation of a defined subset of spinal projection neurons expressing Tacr1 evokes a full repertoire of somatotopically-directed coping behaviors in the absence of noxious input. These cells project to a tiny cluster of Tacr1-positive neurons in the superior lateral parabrachial nucleus (PBN-SL) that themselves are responsive to sustained but not acute noxious stimuli. Activation of these PBN-SLTacr1 neurons alone does not trigger pain responses but instead serves to dramatically heighten nocifensive behaviors and suppress itch. Remarkably, mice with silenced PBN-SLTacr1 neurons ignore long-lasting noxious stimuli. These data reveal a spinoparabrachial pathway that plays a key role in the sensation of ongoing pain.

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