Biology subjects

Smith, L. N.

Publications and source records attributed to Smith, L. N..

3 recordsLinked to original sources

bioRxiv2022

Drug Reinforcement Impairs Cognitive Flexibility by Inhibiting Striatal Cholinergic Neurons

The mechanisms underlying the reduction in cognitive flexibility associated with reinforcement of addictive substance use are unknown. This reinforcement is mediated by substance-induced synaptic plasticity in direct-pathway medium spiny neurons (dMSNs) that project to the substantia nigra (SNr). Cognitive flexibility is mediated by cholinergic interneurons (CINs), which receive extensive local inhibition from the striatum. Here, we report that cocaine or alcohol administration caused a long-lasting potentiation of local inhibitory dMSN[->]CIN transmission in the dorsomedial striatum (DMS), a brain region critical for goal-directed behavior and cognitive flexibility. This dMSN[->]CIN potentiation reduced CIN firing activity. Furthermore, chemogenetic and time-locked optogenetic inhibition of DMS CINs suppressed cognitive flexibility in an instrumental reversal learning task. Importantly, rabies-mediated tracing and physiological studies revealed that SNr-projecting dMSNs, which mediate reinforcement, sent axonal collaterals to inhibit DMS CINs, which mediate flexibility. Our findings demonstrate that the local inhibitory dMSN[->]CIN circuit mediates a reinforcement-induced reduction in cognitive flexibility. HIGHLIGHTSO_LICocaine reinforcement inhibits striatal cholinergic interneurons (CINs) and impairs cognitive flexibility. C_LIO_LIOptogenetic and chemogenetic CIN inhibition impairs cognitive flexibility. C_LIO_LIReinforcement behaviors potentiate inhibitory transmission from direct-pathway medium spiny neurons (dMSNs) to CINs. C_LIO_LISubstantia nigra-projecting dMSNs mediate reinforcement and also send collaterals that inhibit CINs. C_LI

neuroscience↗

bioRxiv2021

Chronic alcohol drinking persistently suppresses thalamostriatal excitation of cholinergic neurons to impair cognitive flexibility

Exposure to addictive substances impairs flexible decision-making. Cognitive flexibility is mediated by striatal cholinergic interneurons (CINs). However, how chronic alcohol drinking alters cognitive flexibility through CINs remains unclear. Here, we report that chronic alcohol consumption and withdrawal impaired reversal of instrumental learning. Chronic alcohol consumption and withdrawal also caused a long-lasting (21 d) reduction of excitatory thalamic inputs onto CINs and reduced pause response of CINs in the dorsomedial striatum (DMS). CINs are known to inhibit glutamatergic transmission in dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) but facilitate this transmission in D2-MSNs, which may contribute to flexible behavior. We discovered that chronic alcohol drinking impaired CIN-mediated inhibition in D1-MSNs and facilitation in D2-MSNs. Importantly, in vivo optogenetic induction of long-term potentiation of thalamostriatal transmission in DMS CINs rescued alcohol-induced reversal learning deficits. These results demonstrate that chronic alcohol drinking reduces thalamic excitation of DMS CINs, compromising their regulation of glutamatergic transmission in MSNs, which may contribute to alcohol-induced impairment of cognitive flexibility. These findings provide a neural mechanism underlying inflexible drinking in alcohol use disorder.

neuroscience↗

bioRxiv2020

The fragile X mental retardation protein promotes adjustments in cocaine self-administration that preserve reinforcement level

The fragile X mental retardation protein (FMRP), an RNA-binding protein, regulates cocaine-induced neuronal plasticity and is critical for the normal development of drug-induced locomotor sensitization, as well as reward-related learning in the conditioned place preference assay. However, it is unknown whether FMRP impacts behaviors that are used to more closely model substance use disorders. Utilizing an intravenous cocaine self-administration (IVSA) assay in Fmr1 knockout (KO) and wild type (WT) littermate mice, we find that, despite normal acquisition and extinction learning, Fmr1 KO mice fail to make a normal upward shift in responding during dose-response testing. Later, with access to the original acquisition dose under increasing schedules of reinforcement (FR1, FR3, FR5), Fmr1 KO mice earn significantly fewer cocaine infusions than WT mice. Importantly, operant conditioning with a palatable food reinforcer does not show similar deficits, indicating that our results do not stem from broad learning or reward-related deficits in Fmr1 KO mice. Additionally, we find an FMRP target, the activity-regulated cytoskeleton-associated protein (Arc), to be significantly reduced in Fmr1 KO mouse synaptic fractions from the nucleus accumbens following cocaine IVSA. Overall, our findings suggest that FMRP facilitates adjustments in drug self-administration behavior that generally serve to preserve reinforcement level, and combined with our similar IVSA findings in Arc KO mice, suggest Arc as a target of FMRP to investigate in behavioral shifts that occur when drug availability is altered.

neuroscience↗