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Browsing by Subject "Nucleus accumbens"

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    Characterizing cellular mechanisms of cocaine-evoked synaptic plasticity in the nucleus accumbens
    (2017-12) Ingebretson, Anna
    Repeated exposure to drugs of abuse alters the structure and function of neural circuits mediating reward, generating maladaptive plasticity in circuits critical for motivated behavior. Within mesocorticolimbic dopamine circuitry, repeated exposure to cocaine induces progressive alterations in AMPAR-mediated glutamatergic synaptic transmission. During abstinence from cocaine treatment, AMPAR signaling is potentiated at synapses on nucleus accumbens (NAc) medium spiny neurons (MSNs), promoting a state of heightened synaptic excitability. Re-exposure to cocaine during abstinence, however, reverses and depotentiates enhanced AMPAR signaling, demonstrating that cocaine bidirectionally alters excitatory synaptic transmission in the NAc. Understanding the neurobiological mechanisms underlying drug-induced synaptic adaptations in the NAc could provide targets for developing strategies to reverse or offset maladaptive processes driving long-lasting vulnerability to relapse. However, the detailed cellular signaling mechanisms mediating cocaine-evoked plasticity have not been well-characterized. Using pharmacological approaches in combination with patch-clamp recordings in the NAc, we investigated the role of candidate signaling factors that mediate adaptive synaptic plasticity in the striatum. Among these, activation of group I metabotropic receptors (mGluR1/5) play a prominent role in synaptic depression at excitatory synapses, and furthermore are implicated in models of relapse to drug-seeking. Consistent with this, we found that activation of mGluR5 is necessary for cocaine-induced depotentiation of AMPAR signaling in the NAc. Downstream of mGluR1/5 receptors, mobilization of endogenous cannabinoids (eCBs) is an important factor modulating excitatory synaptic strength. Dopamine receptors in the striatum also broadly modulate synaptic transmission at glutamatergic terminals on MSNs, and are critically engaged by drugs of abuse. Both dopamine and eCB signaling were necessary factors in the induction of cocaine-induced synaptic plasticity in the NAc, suggesting that these neuromodulators may modify the responsiveness of MSNs to alterations in glutamatergic input induced by cocaine. Finally, we examined plasticity at synapses on specific MSN cell subpopulations, demonstrating that specific dopamine receptors on distinct cell types promote specific modifications in AMPAR synaptic function following cocaine experience. These neuromodulatory signaling mechanisms may serve to gate the induction of plasticity at glutamatergic afferents on NAc MSNs by converging on common factors that control the sensitivity of MSNs to excitatory input, ultimately driving addiction-related behavior.
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    Investigation of Glutamatergic Circuitry Underlying Copulatory Reward in Female Syrian Hamsters
    (2019-01) Moore, Kelsey
    Sex behavior in female mammals is known to involve rewarding consequences that increase the motivation to copulate. I have utilized female hamsters as a model to examine the underlying circuitry and mechanisms of this natural reward. Despite a wealth of information detailing dopaminergic neurotransmission in this region during sexual behavior, the role of glutamate, although the major excitatory neurotransmitter in the brain, has been disproportionately understudied. The goal of this dissertation work was to help close this gap in knowledge to further develop an understanding of the complex underpinnings of female sexual reward and motivation. This understanding is vital in the effort towards evidence-based therapeutic targets in the treatment of disorders of sexual desire in women. In order to determine the role of glutamate in signaling the rewarding properties of sex, I utilized a multi-faceted approach. First, through establishing the use of enzymatic biosensing in the lab, I evaluated glutamate release patterning in key reward regions during sexual behavior in the female hamster. I discovered time-locked glutamate transients specifically in the core of the nucleus accumbens (NAc) in response to penile intromission from the male. Next, I sought to uncover the potential source of this glutamate innervation of the NAc. Immunohistochemical and retrograde tracing analyses determined the involvement of excitatory glutamatergic efferents from the medial prefrontal cortex (mPFC) to the NAc. Then, to determine if mPFC activity was driving the activation of the NAc during female sexual behavior, I employed designer receptors exclusively activated by designer drugs (DREADDs) to selectively inhibit these excitatory mPFC efferents. I demonstrated that this selective inhibition decreases sex-induced activation of the NAc, confirming the importance of the mPFC in driving increased glutamatergic activity in the NAc in response to sexual behavior in the female. The novel findings reported in this body of work demonstrate the involvement of glutamatergic neurotransmission in sexual reward through a prefrontal-accumbal circuit. These are not only exciting additions to the development of a comprehensive model of female sexual reward, but also provide potential targets for therapeutic intervention. Currently there are no effective treatment options for disorders of sexual desire in women and these results provide attractive avenues for pursuing target-specific and clinically-relevant therapies.