Browsing by Subject "Medial prefrontal cortex"

Now showing 1 - 4 of 4
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    Amyloid-β oligomers in the nucleus accumbens decrease motivation via insertion of calcium-permeable AMPA receptors
    (Springer Nature, 2022) Guo, Changyong; Wen, Di; Zhang, Yihong; Mustaklem, Richie; Mustaklem, Basil; Zhou, Miou; Ma, Tao; Ma, Yao-Ying; Pharmacology and Toxicology, School of Medicine
    It is essential to identify the neuronal mechanisms of Alzheimer’s Disease (AD)-associated neuropsychiatric symptoms, e.g., apathy, before improving the life quality of AD patients. Here, we focused on the nucleus accumbens (NAc), a critical brain region processing motivation, also known to display AD-associated pathological changes in human cases. We found that the synaptic calcium permeable (CP)-AMPA receptors (AMPARs), which are normally absent in the NAc, can be revealed by acute exposure to Aβ oligomers (AβOs), and play a critical role in the emergence of synaptic loss and motivation deficits. Blockade of NAc CP-AMPARs can effectively prevent AβO-induced downsizing and pruning of spines and silencing of excitatory synaptic transmission. We conclude that AβO-triggered synaptic insertion of CP-AMPARs is a key mechanism mediating synaptic degeneration in AD, and preserving synaptic integrity may prevent or delay the onset of AD-associated psychiatric symptoms.
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    Converging Effects of Chronic Pain and Binge Alcohol Consumption on Corticostriatal Neurons and the Effects of Acute Alcohol Exposure on the Medial Prefrontal Cortex
    (2024-07) Yin, Yuexi; Atwood, Brady K.; Baucum, AJ; Hopf, Woody; McKinzie, David L.; Sheets, Patrick L.
    Chronic pain and alcohol use disorder (AUD) are highly comorbid, but whether the two conditions share common brain pathways is unclear. Prior work shows that the anterior insular cortex (AIC) is involved in both chronic pain and alcohol use disorder. However, circuit-specific changes elicited by the combination of pain and alcohol use remain understudied. The goal of this work was to elucidate the converging effects of binge alcohol consumption and chronic pain on AIC neurons that send projections to the dorsolateral striatum (DLS). Here, we used the Drinking-in-the-Dark paradigm to model binge-like alcohol drinking in mice that underwent spared nerve injury (SNI). We found that SNI male mice with no prior alcohol exposure consumed less alcohol compared to sham mice. Electrophysiological analyses showed that AIC-DLS neurons from SNI-alcohol male mice displayed increased neuronal excitability and increased frequency of miniature excitatory postsynaptic currents. However, mice exposed to alcohol prior to SNI consumed similar amounts of alcohol compared to sham mice following SNI. Together, our data suggest that the pain and alcohol interaction can sensitize the AIC-DLS circuit in mice, which may be critical in understanding how chronic pain alters motivated behaviors associated with alcohol. My second goal was to assess the acute pharmacological effects of alcohol on prodynorphin-expressing neurons in the prelimbic cortex (PLPdyn+), a subregion of the medial prefrontal cortex (mPFC). Kappa opioid receptor (KOR) system dysregulation contributes to alcohol addiction. Prodynorphin (Pdyn) is the precursor peptide to the endogenous opioid ligand for KORs. Early studies demonstrated that acute alcohol exposure elevates Pdyn mRNA expression in the mPFC. However, its functional effects on Pdyn-expressing neurons are not known. Here, we used whole-cell patch-clamp electrophysiology in acute brain slices and glutamate-uncaging via laser scanning photo to map local excitatory and inhibitory inputs onto PL neurons. We found that acute alcohol increases local inhibitory inputs to both layer 2/3 PLPdyn+ and PLPdyn- neurons but has no effect on excitatory inputs. Under untreated conditions, PLPdyn+ neurons show stronger local excitatory inputs compared to PLPdyn- neurons. Overall, these data suggest that acute alcohol intoxication inhibits intracortical circuit of PL neurons regardless of neuronal subtypes.
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    The reinforcing effects of ethanol within the prelimbic cortex and ethanol drinking: Involvement of local dopamine D2 receptor-mediated neurotransmission
    (Elsevier, 2020-09) Engleman, Eric A.; Ingraham, Cynthia M.; Rodd, Zachary A.; Murphy, James M.; McBride, William J.; Ding, Zheng-Ming; Psychiatry, School of Medicine
    Previous studies have identified important mesolimbic regions in supporting the reinforcing effects of ethanol. However, the involvement of the medial prefrontal cortex (mPFC), another key region within the mesocorticolimbic system, in ethanol reinforcement has been understudied. The objective of the current study was to examine the role of the prelimbic (PL) cortex sub-region of the mPFC in ethanol reinforcement and drinking. Intracranial self-administration was used to examine the reinforcing effects of ethanol within the PL cortex. Quantitative microdialysis was used to measure basal extracellular DA concentrations and clearance in the PL cortex following chronic ethanol drinking. In addition, the involvement of dopamine (DA) D2 receptors within the PL cortex on the reinforcing effects of ethanol and ethanol drinking was determined. Ethanol was dose-dependent self-administered into the PL cortex, with significantly more infusions elicited by 100-200 mg% ethanol than vehicle. Co-infusion of the D2 receptor antagonist sulpiride significantly reduced ethanol self-administration. Chronic ethanol drinking significantly elevated basal extracellular DA concentrations without altering DA clearance. Microinjection of sulpiride into the PL cortex selectively reduced ethanol, but not saccharine, drinking. These results indicate that the PL cortex supported the reinforcing effects of ethanol, and that ethanol drinking enhanced basal DA neurotransmission within the PL cortex. In addition, D2 receptor antagonism within the PL cortex reduced ethanol self-administration and drinking. Collectively, these findings revealed important DA mechanisms within the PL cortex in mediating ethanol reinforcement and drinking.
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    The stimulating effects of ethanol on ventral tegmental area dopamine neurons projecting to the ventral pallidum and medial prefrontal cortex in female Wistar rats: regional difference and involvement of serotonin-3 receptors
    (Springer, 2011-07) Ding, Zheng-Ming; Oster, Scott M.; Hall, Sarah R.; Engleman, Eric A.; Hauser, Sheketha R.; McBride, William J.; Rodd, Zachary A.; Psychiatry, School of Medicine
    RATIONALE: The ventral tegmental area (VTA) mediates the local stimulating effects of ethanol (EtOH) in a region-dependent manner, with EtOH administration in the posterior but not anterior VTA stimulating the mesolimbic system. The serotonin-3 (5-HT(3)) receptor has been involved in the effects of EtOH on the mesolimbic system. OBJECTIVES: The current study tested the hypothesis that EtOH would stimulate mesopallidal and mesocortical dopamine neurons in the posterior but not anterior VTA and that the stimulating effects of EtOH in the VTA would involve activation of local 5-HT(3) receptors. METHODS: Wistar female rats were surgically implanted with two cannulae, one in one sub-region of the VTA for microinjection and the other in the ventral pallidum (VP) or medial prefrontal cortex (mPFC) for microdialysis. Artificial cerebrospinal fluid or EtOH (200 mg%; 44 mM) was microinjected in the anterior or posterior VTA, and extracellular dopamine was measured in the VP or mPFC with microdialysis-HPLC. RESULTS: EtOH injections in the posterior but not anterior VTA significantly increased extracellular dopamine levels in the VP and mPFC. Co-injections of the 5-HT(3) receptor antagonist ICS-205,930 with EtOH in the posterior VTA significantly reduced the effects of EtOH on extracellular dopamine levels in the VP and mPFC. CONCLUSIONS: The results indicate that posterior VTA dopamine neurons projecting to the VP and mPFC are stimulated by local administration of EtOH and that the local stimulating effects of EtOH are mediated, at least in part, by 5-HT(3) receptors.