Neuroscience
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Fear memories allow animals to recognize and adequately respond to dangerous situations. The prelimbic cortex (PrL) is a crucial node in the circuitry that encodes contextual fear memory, and its activity is central for fear memory expression over time. However, while PrL has been implicated in contextual fear memory storage, the molecular mechanisms underlying its maintenance remain unclear. ⋯ Also, PKMζ inhibition in the PrL does not impair the maintenance of recent contextual fear memory. However, we found that inhibition of prelimbic PKMζ at a remote time point disrupts contextual fear memory maintenance, and that blocking GluA2-dependent removal of AMPARs prevents this impairment. Our results confirm the central role of PrL in fear memory and identify PKMζ-induced inhibition of GluA2-containing AMPAR endocytosis as a key mechanism governing remote contextual fear memory maintenance.
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The ventral midbrain is the primary source of dopamine- (DA) expressing neurons in most species. GABA-ergic and glutamatergic cell populations are intermixed among DA-expressing cells and purported to regulate both local and long-range dopamine neuron activity. Most work has been conducted in rodent models, however due to evolutionary expansion of the ventral midbrain in primates, the increased size and complexity of DA subpopulations warrants further investigation. ⋯ Putative GABAergic neurons were fewer overall, and evenly dispersed across the DA subpopulations (GAD67 = 71,215 ± 5663; A10 = 16,836 ± 2743; A9 = 24,855 ± 3144 and A8 = 12,633 ± 3557). Calculating the GAD67/TH ratio for each subregion revealed differential balances of these two cell types across the DA subregions. The A8 subregion had the highest complement of GAD67-positive neurons compared to TH-positive neurons (1:1), suggesting a potentially high capacity for GABAergic inhibition of DA output in this region.
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Varicella zoster virus (VZV) is responsible for chronic pain. VZV injection has similarities to herpes zoster (HZ) "shingles" pain in humans. In this study orofacial pain was induced by injecting male rats with the human VZV. ⋯ Attenuating Nrxn3 expression also increases VZV associated orofacial pain. Activating GABAergic neurons within the central amygdala with opsins increase GABA release in the parabrachial and reduced the pain response after Nrxn3 shRNA treatment. These results are consistent with the idea that Nrxn3 within the central amygdala controls VZV associated pain by regulating GABA release in the lateral parabrachial that then controls the activity of ascending pain neurons.
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Disturbance in synaptic excitatory and inhibitory (E/I) transmission in the prefrontal cortex is considered a critical factor for cognitive dysfunction, a core symptom in schizophrenia. However, the cortical network pathophysiology induced by E/I imbalance is not well characterized, and an effective therapeutic strategy is lacking. In this study, we simulated imbalanced cortical network by using mice with parvalbumin neuron (PV) specific knockout of GluA1 (AMPA receptor subunit 1) (Gria1-PV KO) as an experimental model. ⋯ Our results suggest that PV-specific deletion of GluA1 might be an experimental approach for back translating the E/I imbalance observed in schizophrenic patients. Our work offers a systematic workflow to understand the effect of GlyT1 inhibition in restoring cortical network activity from single cells to local brain circuitry. This study highlights that selectively boosting NMDA receptor-mediated excitatory drive to enhance the network inhibitory transmission from interneurons to pyramidal neurons (PYs) is a potential therapeutic strategy for restoring E/I imbalance-associated cognitive-related abnormality.