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 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 Embryonic Origin of the Islet1 and Pax6 Neurons of the Chicken Central Extended Amygdala Using Cell Migration Assays and Relation to Different Neuropeptide-Containing Cells

2015 ◽  
Vol 85 (3) ◽  
pp. 139-169 ◽  
Author(s):  
Alba Vicario ◽  
Antonio Abellán ◽  
Loreta Medina
Keyword(s):  
Transcription Factors ◽  
Cell Migration ◽  
Published Data ◽  
Stria Terminalis ◽  
Dorsal Part ◽  
Medial Region ◽  
Bed Nucleus ◽  
Extended Amygdala ◽  
Embryonic Origin ◽  
Migration Assays

In a recent study, we tentatively identified different subdivisions of the central extended amygdala (EAce) in chicken based on the expression of region-specific transcription factors (including Pax6 and Islet1) and several phenotypic markers during embryonic development. Such a proposal was partially based on the suggestion that, similarly to the subdivisions of the EAce of mammals, the Pax6 and Islet1 neurons of the comparable chicken subdivisions derive from the dorsal (Std) or ventral striatal embryonic domains (Stv), respectively. To investigate whether this is true, in the present study, we carried out cell migration assays from chicken Std or Stv combined with immunofluorescence for Pax6 or Islet1. Our results showed that the cells of the proposed chicken EAce truly originate in either Std (expressing Pax6) or Stv (expressing Islet1). This includes lateral subdivisions previously compared to the intercalated amygdalar cells and the central amygdala of mammals, also rich in Std-derived Pax6 cells and/or Stv-derived Islet1 cells. In the medial region of the chicken EAce, the dorsal part of the lateral bed nucleus of the stria terminalis (BSTL) contains numerous cells expressing Nkx2.1 (mostly derived from the pallidal domain), but our migration assays showed that it also contains neuron subpopulations from the Stv (expressing Islet1) and Std (expressing Pax6), resembling the mouse BSTL. These findings, together with those previously published in different species of mammals, birds and reptiles, support the homology of the chicken EAce to that of other vertebrates, and reinforce the existence of several cell subcorridors inside the EAce. In addition, together with previously published data on neuropeptidergic cells, these results led us to propose the existence of at least seventeen neuron subtypes in the EAce in rodents and/or some birds (chicken and pigeon). The functional significance and the evolutionary origin of each subtype needs to be analyzed separately, and such studies are mandatory in order to understand the multifaceted modulation by the EAce of fear responses, ingestion, motivation and pain in different vertebrates.

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 Extended amygdala-parabrachial circuits alter threat assessment to regulate feeding

2020 ◽  
Author(s):  
Dionnet L. Bhatti ◽  
Andrew T. Luskin ◽  
Christian E. Pedersen ◽  
Bernard Mulvey ◽  
Hannah Oden-Brunson ◽  
...  
Keyword(s):  
Neural Circuit ◽  
Threat Assessment ◽  
Threat Detection ◽  
Stria Terminalis ◽  
Bed Nucleus ◽  
Environmental Threats ◽  
Extended Amygdala ◽  
Evolutionarily Conserved ◽  
Evolutionary Success ◽  
Affective Information

AbstractAn animal’s evolutionary success depends on the ability to seek and consume foods while avoiding environmental threats. However, how evolutionarily conserved threat detection circuits modulate feeding is unknown. In mammals, feeding and threat assessment are strongly influenced by the parabrachial nucleus (PBN), a structure that responds to threats and inhibits feeding. Here, we report that the PBN receives dense inputs from the bed nucleus of the stria terminalis (BNST), an extended amygdala structure that encodes affective information. Using a series of complementary approaches, we identify opposing BNST-PBN circuits that modulate a genetically-defined population of PBN neurons to control feeding. This previously unrecognized neural circuit integrates threat assessment with the intrinsic drive to eat.

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 Dysregulation of Nociceptin/Orphanin FQ and Dynorphin Systems in the Extended Amygdala of Alcohol Preferring Marchigian Sardinian (msP) Rats

2021 ◽  
Vol 22 (5) ◽  
pp. 2448
Author(s):  
Francesca Felicia Caputi ◽  
Serena Stopponi ◽  
Laura Rullo ◽  
Martina Palmisano ◽  
Massimo Ubaldi ◽  
...  
Keyword(s):  
Stress Responses ◽  
Alcohol Intake ◽  
Negative Mood ◽  
Alcohol Exposure ◽  
Stria Terminalis ◽  
Orphanin Fq ◽  
Bed Nucleus ◽  
Extended Amygdala ◽  
Negative Condition ◽  
Trk B

Previous studies have shown that genetically selected Marchigian Sardinian alcohol-preferring (msP) rats consume excessive amounts of ethanol to self-medicate from negative moods and to relieve innate hypersensitivity to stress. This phenotype resembling a subset of alcohol use disorder (AUD) patients, appears to be linked to a dysregulation of the equilibrium between stress and antistress mechanisms in the extended amygdala. Here, comparing water and alcohol exposed msP and Wistar rats we evaluate the transcript expression of the anti-stress opioid-like peptide nociceptin/orphanin FQ (N/OFQ) and its receptor NOP as well as of dynorphin (DYN) and its cognate κ-opioid receptor (KOP). In addition, we measured the transcript levels of corticotropin-releasing factor (CRF), CRF receptor 1 (CRF1R), brain-derived neurotrophic factor (BDNF) and of the tropomyosin receptor kinase B receptor (Trk-B). Results showed an innately up-regulation of the CRFergic system, mediating negative mood and stress responses, as well as an inherent up-regulation of the anti-stress N/OFQ system, both in the amygdala (AMY) and bed nucleus of the stria terminalis (BNST) of msP rats. The up-regulation of this latter system may reflect an attempt to buffer the negative condition elicited by the hyperactivity of pro-stress mechanisms since results showed that voluntary alcohol consumption dampened N/OFQ. Alcohol exposure also reduced the expression of dynorphin and CRF transmissions in the AMY of msP rats. In the BNST, alcohol intake led to a more complex reorganization of these systems increasing receptor transcripts in msP rats, along with an increase of CRF and a decrease of N/OFQ transcripts, respectively. Moreover, mimicking the effects of alcohol in the AMY we observed that the activation of NOP receptor by intracerebroventricular administration of N/OFQ in msP rats caused an increase of BDNF and a decrease of CRF transcripts. Our study indicates that both stress and anti-stress mechanisms are dysregulated in the extended AMY of msP rats. The voluntary alcohol drinking, as well as NOP agonism, have a significant impact on neuropeptidergic systems arrangement, bringing the systems back to normalization.

scholarly journals Intrinsic functional connectivity of the central extended amygdala

2017 ◽  
Author(s):  
Rachael M. Tillman ◽  
Melissa D. Stockbridge ◽  
Brendon M. Nacewicz ◽  
Salvatore Torrisi ◽  
Andrew S. Fox ◽  
...  
Keyword(s):  
Functional Connectivity ◽  
High Precision ◽  
Community Dwelling ◽  
Central Nucleus ◽  
Stria Terminalis ◽  
Bed Nucleus ◽  
Extended Amygdala ◽  
Intrinsic Functional Connectivity ◽  
Multiband Imaging ◽  
Fear And Anxiety

ABSTRACTThe central extended amygdala (EAc)—including the bed nucleus of the stria terminalis (BST) and central nucleus of the amygdala (Ce)—plays a key role in orchestrating states of fear and anxiety and is implicated in the development and maintenance of anxiety disorders, depression, and substance abuse. Although it is widely thought that these disorders reflect the coordinated actions of large-scale functional circuits in the brain, the architecture of the EAc functional network, and the degree to which the BST and the Ce show distinct patterns of intrinsic functional connectivity, remains incompletely understood. Here, we leveraged a combination of approaches to trace the connectivity of the BST and the Ce in 130 psychiatrically healthy, racially diverse, community-dwelling adults with enhanced power and precision. Multiband imaging, high-precision data registration techniques, and spatially unsmoothed data were used to maximize anatomical specificity. Using newly developed seed regions, whole-brain regression analyses revealed robust functional connectivity between the BST and Ce via the sublenticular extended amygdala (‘substantia innominata’), the ribbon of subcortical gray matter encompassing the ventral amygdalofugal pathway. Both regions displayed significant coupling with the ventromedial prefrontal cortex (vmPFC), midcingulate cortex (MCC), insula, and anterior hippocampus. The BST showed significantly stronger connectivity with prefrontal territories—including the vmPFC, anterior MCC and pregenual anterior cingulate cortex—as well as the thalamus, striatum, and the periaqueductal gray. The only regions showing stronger functional connectivity with the Ce were located in the anterior hippocampus and dorsal amygdala. These observations provide a baseline against which to compare a range of special populations, inform our understanding of the role of the EAc in normal and pathological fear and anxiety, and highlight the value of several new approaches to image registration which may be particularly useful for researchers working with ‘de-identified’ neuroimaging data.GRAPHICAL ABSTRACTIntrinsic functional connectivity of bed nucleus of the stria terminalis (BST) and the central nucleus of the amygdala (Ce) in 130 psychiatrically healthy adults.HIGHLIGHTSBST and Ce implicated in normal and pathological fear and anxietyTraced the intrinsic functional connectivity of the BST and the Ce in 130 adultsMultiband imaging, high-precision registration, unsmoothed data, newly developed seedsBST and Ce show robust coupling with one another, hippocampus, insula, MCC, and vmPFCBST shows stronger coupling with prefrontal/cingulate territories and brainstem/PAG

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