Browsing by Subject "Striatum"
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Item Characterizing cellular mechanisms of cocaine-evoked synaptic plasticity in the nucleus accumbens(2017-12) Ingebretson, AnnaRepeated 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.Item A novel molecular mechanism of stress peptide action in neurons.(2010-12) Stern, Christopher MichaelStress is any actual or perceived disturbance of an organism’s environment. The acute response to stress includes the release of corticotropin-releasing factor (CRF) from the hypothalamus to activate the pituitary and downstream glucocorticoid secretion. In addition to this classical role, CRF also influences many extra-hypothalamic brain regions including the striatum and the hippocampus. CRF and the related stress peptide Urocortin 1 (UCN) exert their cellular effects by binding to one of two cognate G-protein coupled receptors (GPCRs), CRF receptor 1 (CRFR1) or 2 (CRFR2). While these GPCRs were initially characterized as being coupled to adenylyl cyclase, cAMP and PKA signaling, it has since become clear that CRFRs couple to numerous intracellular signaling cascades. Here, I describe work elucidating the intracellular signaling pathways by which stress peptides influence both striatal and hippocampal neurons. This document describes a novel intracellular signaling pathway whereby CRF and UCN lead to a rapid Gβγ-dependent increase in phosphorylation of the activity-dependent transcription factor CREB. These data not only describe a completely original mechanism of stress peptide signaling in neurons, but also include the first direct demonstrations of Gβγ-mediated CREB phosphorylation in any cellular system. Together, these results suggest that stress peptide influence of Gβγ signaling may be a fundamental, yet underexplored, molecular mechanism by which stress influences both the central nervous system and other stresspeptide sensitive tissues.