2009 — 2011 |
Root, David H |
F31Activity Code Description: To provide predoctoral individuals with supervised research training in specified health and health-related areas leading toward the research degree (e.g., Ph.D.). |
Neurophysiology of Cocaine-Seeking Behavior @ Rutgers, the State Univ of N.J.
DESCRIPTION (provided by applicant): There are currently no effective pharmacological or behavioral treatments for cocaine addiction. One possible explanation is that the neural correlates of drug-seeking are poorly understood. Understanding the neurophysiology of cocaine-seeking may enable the development of treatments aimed at altering the activity of neurons important for generating these behaviors. One brain region critical for cocaine-seeking behavior is the nucleus accumbens (NAcc). Over the past ten years, our lab has found several correlates of cocaine- seeking encoded by single NAcc neurons during drug and drug-free states. However, cocaine addiction is a complicated disorder that is likely encoded by other brain regions. Since most neurophysiological studies were localized to the NAcc there is a paucity of physiological data supporting this assertion. One region likely to encode cocaine-seeking is the ventral pallidum (VP). The NAcc primarily and massively projects to the VP. Similar to the NAcc, VP lesions decrease cocaine-seeking behavior. However, there has been no neurophysiological investigation into the encoding of cocaine-seeking behavior by VP neurons. In order to address this discrepancy, we will simultaneously record NAcc and VP neurons during cocaine-self administration as well as cocaine-seeking following a period of abstinence in which cocaine-associated cues are noncontingently presented. Such data will be important for understanding the role of VP neurons during binge and relapse behavior. Since the vast majority of NAcc projection neurons are GABAergic (e.g., inhibitory), NAcc neuron firing may be inversely related to VP neuron firing. However, recent reports of VP neurons during sucrose-seeking behavior suggest this may not be the case. The majority of NAcc neurons show increases in firing rate in response to a cocaine predictive cue;a similar majority of VP neurons display increases in firing rate in response to a food predictive cue. A GABAergic inverse relationship of NAcc-VP firing predicts predominant decreases in VP neuron firing in response to cocaine predictive cues. The direction, magnitude, and prevalence of VP subregional neurons during cocaine-seeking behaviors and cue-reactivity will be assessed and compared with previously as well as simultaneously recorded NAcc subregional neurons. Spike triggered averaging of simultaneously recorded NAcc and VP neurons will provide insight into behavior-induced firing patterns. Our preliminary results suggest that VP neurons encode cocaine self-administration behavior heterogenously. Since cocaine addiction is typified by cycles of binging and abstinence, and cues produce cravings, our examination of the neurophysiological correlates of cocaine-seeking and cue-reactivity under drug and abstinent conditions may enable insight into the disorder.
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0.915 |
2020 |
Root, David H |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Genetic Dissection of Ventral Tegmental Area Glutamate and Gaba Neurons in Reward and Aversion
Project Summary / Abstract The ventral tegmental area (VTA) controls the motivation to pursue rewards and avoid harmful stimuli. Within the last decade it has been shown that the VTA is populated by neurons that release the neuromodulator dopamine, neurons that release the inhibitory neurotransmitter GABA, and neurons that release the excitatory neurotransmitter glutamate. Based on the use of optogenetic techniques to manipulate dopamine, GABA, or glutamate neurons, current models of VTA function postulate that reward and aversion-based motivation is mediated by heterogeneous types of VTA neurons and their discrete neuronal networks. However, we have recently discovered an unanticipated type of neuron in the VTA, those that release both glutamate and GABA. The discovery of the VTA glutamate-GABA neurons redefines the GABA-releasing and glutamate-releasing VTA cell-types by multiple genetic features: release of glutamate without GABA (glutamate-only neurons), release of GABA without glutamate (GABA-only neurons), or release of both (glutamate-GABA neurons). While optogenetic studies have shown roles of glutamate-releasing or GABA-releasing neurons in motivated behavior, the redefinition of VTA glutamate and GABA-releasing neurons into three subtypes indicates that our understanding of the VTA cell-type specific roles in motivated behavior is incomplete. We will use novel intersectional and subtractive genetic and viral tools to identify the neuronal networks and roles in reward- or aversion-mediated behavior of VTA glutamate-GABA, glutamate-only, and GABA-only neurons and circuits. In Aim 1, we will comprehensively map the brain-wide inputs and outputs of VTA glutamate-GABA, glutamate- only, and GABA-only neurons using cell-type specific anterograde tracing and monosynaptic retrograde tracing with a modified rabies virus. In Aim 2, using the genetically encoded calcium indicator GCaMP6 we will identify the neuronal activity patterns of VTA glutamate-GABA, glutamate-only, and GABA-only neurons, as well as the neuronal activity patterns of major afferents that target each genetically separate VTA cell-type, in response to rewarding and aversive stimuli and their predictors. Finally, we will optogenetically stimulate or inhibit VTA glutamate-GABA, glutamate-only, and GABA-only neurons and circuits to define their causal contributions towards motivated behavior. Preliminary data support the hypothesis that VTA glutamate-GABA, glutamate- only, and GABA-only neurons have distinct neuronal networks and motivational functions. Together, these studies will comprehensively redefine the motivational functions of VTA neurons and their individual circuits. Results will provide new directions to alleviate reward and aversion based disorders such as addiction.
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