Kristen E. Pleil

Bio: Kristen E. Pleil is an academic researcher from Cornell University. The author has contributed to research in topics: Stria terminalis & Binge drinking. The author has an hindex of 22, co-authored 37 publications receiving 2360 citations. Previous affiliations of Kristen E. Pleil include Duke University & University of North Carolina at Chapel Hill.

Distinct extended amygdala circuits for divergent motivational states

Abstract: The co-morbidity of anxiety and dysfunctional reward processing in illnesses such as addiction and depression suggests that common neural circuitry contributes to these disparate neuropsychiatric symptoms. The extended amygdala, including the bed nucleus of the stria terminalis (BNST), modulates fear and anxiety, but also projects to the ventral tegmental area (VTA), a region implicated in reward and aversion, thus providing a candidate neural substrate for integrating diverse emotional states. However, the precise functional connectivity between distinct BNST projection neurons and their postsynaptic targets in the VTA, as well as the role of this circuit in controlling motivational states, have not been described. Here we record and manipulate the activity of genetically and neurochemically identified VTA-projecting BNST neurons in freely behaving mice. Collectively, aversive stimuli exposure produced heterogeneous firing patterns in VTA-projecting BNST neurons. By contrast, in vivo optically identified glutamatergic projection neurons displayed a net enhancement of activity to aversive stimuli, whereas the firing rate of identified GABAergic (γ-aminobutyric acid-containing) projection neurons was suppressed. Channelrhodopsin-2-assisted circuit mapping revealed that both BNST glutamatergic and GABAergic projections preferentially innervate postsynaptic non-dopaminergic VTA neurons, thus providing a mechanistic framework for in vivo circuit perturbations. In vivo photostimulation of BNST glutamatergic projections resulted in aversive and anxiogenic behavioural phenotypes. Conversely, activation of BNST GABAergic projections produced rewarding and anxiolytic phenotypes, which were also recapitulated by direct inhibition of VTA GABAergic neurons. These data demonstrate that functionally opposing BNST to VTA circuits regulate rewarding and aversive motivational states, and may serve as a crucial circuit node for bidirectionally normalizing maladaptive behaviours.

Chronic alcohol remodels prefrontal neurons and disrupts NMDAR-mediated fear extinction encoding

Abstract: Alcoholism is frequently co-morbid with post-traumatic stress disorder, but it is unclear how alcohol affects the neural circuits mediating recovery from trauma. We found that chronic intermittent ethanol (CIE) impaired fear extinction and remodeled the dendritic arbor of medial prefrontal cortical (mPFC) neurons in mice. CIE impaired extinction encoding by infralimbic mPFC neurons in vivo and functionally downregulated burst-mediating NMDA GluN1 receptors. These findings suggest that alcohol may increase risk for trauma-related anxiety disorders by disrupting mPFC-mediated extinction of fear.

NPY signaling inhibits extended amygdala CRF neurons to suppress binge alcohol drinking

Abstract: Binge alcohol drinking is a tremendous public health problem because it leads to the development of numerous pathologies, including alcohol abuse and anxiety. It is thought to do so by hijacking brain systems that regulate stress and reward, including neuropeptide Y (NPY) and corticotropin-releasing factor (CRF). The central actions of NPY and CRF have opposing functions in the regulation of emotional and reward-seeking behaviors; thus, dysfunctional interactions between these peptidergic systems could be involved in the development of these pathologies. We used converging physiological, pharmacological and chemogenetic approaches to identify a precise neural mechanism in the bed nucleus of the stria terminalis (BNST), a limbic brain region involved in pathological reward and anxiety behaviors, underlying the interactions between NPY and CRF in the regulation of binge alcohol drinking in both mice and monkeys. We found that NPY Y1 receptor (Y1R) activation in the BNST suppressed binge alcohol drinking by enhancing inhibitory synaptic transmission specifically in CRF neurons via a previously unknown Gi-mediated, PKA-dependent postsynaptic mechanism. Furthermore, chronic alcohol drinking led to persistent alterations in Y1R function in the BNST of both mice and monkeys, highlighting the enduring, conserved nature of this effect across mammalian species. Together, these data provide both a cellular locus and signaling framework for the development of new therapeutics for treatment of neuropsychiatric diseases, including alcohol use disorders.

Corticotropin Releasing Factor Signaling in the Central Amygdala is Recruited during Binge-Like Ethanol Consumption in C57BL/6J Mice

Abstract: A well established body of work indicates a crucial role for corticotropin-releasing factor (CRF) in neurobiological responses associated with excessive dependence-like ethanol drinking in ethanol-vapor-exposed rodents. Recent evidence demonstrates a role for CRF in the modulation of binge-like ethanol consumption by nondependent mice, a behavior that can precede ethanol dependence. The CRF circuitry that is engaged by binge-like ethanol exposure, however, is unknown. Using converging approaches, we provide evidence that, similar to ethanol-vapor-induced increases in ethanol intake, CRF signaling in the central nucleus of the amygdala (CeA) is engaged during binge-like ethanol consumption by C57BL/6J mice. Specifically, we found that binge-like consumption of an ethanol solution (20% ethanol v/v) was attenuated by pretreatment with the CRF1R antagonists antalarmin, 4-ethyl-[2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino-1-butanol, and NBI-27914 at doses (30 mg/kg, i.p.) that did not alter nonbinge-like ethanol consumption. Binge-like ethanol consumption resulted in significant increases of CRF immunoreactivity in the CeA immediately following ethanol drinking and 18-24 h following ethanol removal and also blocked the ability of CRF to enhance GABAergic transmission in the CeA 18-24 h following ethanol removal. Pretreatment with bilateral injections of antalarmin (1 μg/0.5 μl per side) into the CeA, but not the adjacent basolateral amygdala, significantly attenuated binge-like ethanol consumption. These findings suggest that CRF signaling in the CeA is recruited during excessive ethanol intake, before the development of dependence. We hypothesize that plastic changes in CRF signaling develop with repeated binge-like drinking episodes, contributing to the transition to dependence.

Neuroscience 細胞死：最近の知見

Abstract: 中枢神経系疾患の治療は正常細胞（ニューロン）の機能維持を目的とするが，脳血管障害のように機能障害の原因が細胞の死滅に基づくことは多い．一方，脳腫瘍の治療においては薬物療法や放射線療法といった腫瘍細胞の死滅を目標とするものが大きな位置を占める．いずれの場合にも，細胞死の機序を理解することは各種病態や治療法の理解のうえで重要である．現在のところ最も研究の進んでいる細胞死の型はアポトーシスである．そのなかで重要な位置を占めるミトコンドリアにおける反応および抗アポトーシス因子について概要を紹介する．

From circuits to behaviour in the amygdala

Abstract: The amygdala has long been associated with emotion and motivation, playing an essential part in processing both fearful and rewarding environmental stimuli. How can a single structure be crucial for such different functions? With recent technological advances that allow for causal investigations of specific neural circuit elements, we can now begin to map the complex anatomical connections of the amygdala onto behavioural function. Understanding how the amygdala contributes to a wide array of behaviours requires the study of distinct amygdala circuits.

Role of WHO.

Abstract: OVERVIEW The GRA Marketing Internship Program is offered to students who are interested in gaining valuable work experience through efforts in marketing, membership, sales, and events. Interns work directly to assist the Director of Marketing and Communications on various tasks relating to upcoming GRA events. During this internship, students will work a minimum of 10 hours a week and a maximum of 20 hours a week. Students are encouraged to earn credit for their internship, however this is a paid internship. Students interested in obtaining credit for their internship must consult their academic advisor or the intern coordinator at their academic unit.

Neuronal circuits for fear and anxiety

Abstract: Decades of research has identified the brain areas that are involved in fear, fear extinction, anxiety and related defensive behaviours. Newly developed genetic and viral tools, optogenetics and advanced in vivo imaging techniques have now made it possible to characterize the activity, connectivity and function of specific cell types within complex neuronal circuits. Recent findings that have been made using these tools and techniques have provided mechanistic insights into the exquisite organization of the circuitry underlying internal defensive states. This Review focuses on studies that have used circuit-based approaches to gain a more detailed, and also more comprehensive and integrated, view on how the brain governs fear and anxiety and how it orchestrates adaptive defensive behaviours.