Biology subjects

Chappell, A. M.

Publications and source records attributed to Chappell, A. M..

3 recordsLinked to original sources

bioRxiv2019

Chronic Ethanol Differentially Modulates Glutamate Release from Dorsal and Ventral Prefrontal Cortical Inputs onto Rat Basolateral Amygdala Principal Neurons

The medial prefrontal cortex (mPFC) and the basolateral amygdala (BLA) have strong reciprocal connectivity. Projections from the BLA to the mPFC can bidirectionally modulate anxiety-related behaviors but it is unclear if the same is true for mPFC to BLA projections. Our laboratory is specifically interested in withdrawal-related anxiety-like behavior and the underlying synaptic plasticity. Here, we use optogenetics and chemogenetics to characterize the neurophysiological and behavioral alterations produced by chronic ethanol exposure and withdrawal on dorsal mPFC/prelimbic (dmPFC/PL) and ventral mPFC (vmPFC/IL) terminals in the BLA. We exposed adult male Sprague-Dawley rats to chronic intermittent ethanol (CIE) using vapor chambers, measured anxiety-like behavior on the elevated zero maze (EZM), and used electrophysiology to record glutamatergic and GABAergic responses in BLA principal neurons. We found that 24-hour withdrawal following a 7-day CIE exposure significantly increased the glutamate release probability from PL/dmPFC terminals, but significantly decreases the glutamate release probability from IL/vmPFC terminals. Chemogenetic inhibition of PL/dmPFC terminals in the BLA attenuated the increased withdrawal-dependent, anxiety-like behavior. These data demonstrate that chronic ethanol exposure and withdrawal strengthens the PL/dmPFC - BLA pathway but weakens the IL/vmPFC - BLA pathway. Moreover, we provide novel evidence that the PL/dmPFC - BLA pathway can modulate anxiety-like behavior. These findings suggest that mPFC-BLA circuits known to regulate the acquisition of aversive behaviors are up-regulated by chronic ethanol while those involved with the extinction of these behaviors are down-regulated. Significance StatementAccumulating evidence suggests that the medial prefrontal cortex and its projections to the basolateral amygdala bidirectionally modulate fear-related behaviors. Since the neuronal circuits for fear and anxiety are thought to overlap, we sought to examine the role of prelimbic and infralimbic subdivisions of the medial prefrontal cortex and their inputs to the basolateral amygdala in regulating anxiety. Specifically, we focused on alcohol withdrawal-induced anxiety-like behavior, which is a commonly reported cause of relapse in human alcoholics. In our study, we used optogenetics and chemogenetics to demonstrate, for the first time, that withdrawal from chronic ethanol exposure strengthens prelimbic synapses, but weakens infralimbic synapses in the basolateral amygdala and that inhibiting glutamate release from prelimbic terminal in the basolateral amygdala reduces anxiety-like behavior.

neuroscience↗

bioRxiv2019

Polymodal Sensory Thalamic Inputs to the Rat Lateral Amygdala are Facilitated by Chronic Ethanol Exposure and Regulate Withdrawal-associated Anxiety

Thalamic projections to the lateral amygdala regulate the acquisition of conditioned aversive and reward-related behaviors. Recent work suggests that exposure to chronic ethanol up-regulates presynaptic function of lateral amygdala stria terminalis inputs which contain projections from somatosensory thalamic nuclei. To understand potential contributions by thalamic inputs and their role in the expression of withdrawal-associated aversive behaviors, we integrated optogenetic and chemogenetic approaches with in vitro measures of synaptic function and anxiety-like behavior. We found that expression of Channelrhodopsin in the caudal extension of the posterior thalamic group (cPO) produced monosynaptic glutamatergic synaptic responses in lateral amygdala principal neurons that could be inhibited by co-expression of the hM4-Gi-DREADD. Chronic ethanol exposure increased glutamate release from these cPO terminals but did not impact inhibition by the DREADD agonist, CNO. Systemic injection of CNO specifically reduced withdrawal-related increases in anxiety-like behaviors in animals expressing the Gi-DREADD in cPO. And, microinjection of CNO directly into the lateral amygdala mimicked this anti-anxiety effect. These findings suggest that the cPO-LA circuit is vulnerable to chronic ethanol exposure and plays an important role in regulating anxiety-like behavior following chronic ethanol exposure.

neuroscience↗

bioRxiv2019

Chemogenetic inhibition of a monosynaptic projection from the basolateral amygdala to the ventral hippocampus reduces appetitive and consummatory alcohol drinking behaviors

Alcohol use disorder (AUD) and anxiety/stressor disorders frequently co-occur and this dual diagnosis represents a major health and economic problem worldwide. The basolateral amygdala (BLA) is a key brain region that is known to contribute to the etiology of both disorders. Although many studies have implicated BLA hyperexcitability in the pathogenesis of AUD and comorbid conditions, relatively little is known about the specific efferent projections from this brain region that contribute to these disorders. Recent optogenetic studies have shown that the BLA sends a strong monosynaptic excitatory projection to the ventral hippocampus (vHC) and that this circuit modulates anxiety- and fear-related behaviors. However, it is not known if this pathway influences alcohol drinking-related behaviors. Here, we employed a rodent operant drinking regimen that procedurally separates appetitive (e.g. seeking) and consummatory (e.g. intake) behaviors, chemogenetics, and brain region-specific microinjections, to determine if BLA-vHC circuitry influences alcohol drinking-related measures. We first confirmed prior optogenetic findings that silencing this circuit reduced anxiety-like behaviors on the elevated plus-maze. We then demonstrated that inhibiting the BLA-vHC pathway significantly reduced appetitive alcohol drinking-related behaviors while having no effect on consummatory measures. Sucrose seeking measures were also reduced following chemogenetic inhibition of this circuit. Taken together, these findings provide the first indication that the BLA-vHC circuit may regulate appetitive alcohol drinking-related behaviors and add to a growing body of evidence suggesting that dysregulation of this pathway may contribute to the pathophysiology of AUD and anxiety/stressor-related disorders. HIGHLIGHTSO_LIThe basolateral amygdala sends a monosynaptic glutamatergic projection to the ventral hippocampus C_LIO_LIInhibiting this circuit reduces anxiety-like behaviors in male Long Evans rats C_LIO_LIInhibition of this pathway also decreases operant alcohol seeking-related behaviors C_LI

neuroscience↗