Downregulation of Synaptotagmin 1 in the Prelimbic Cortex Drives Alcohol-Associated Behaviors in Rats

Abstract

BACKGROUND: Alcohol addiction is characterized by persistent neuroadaptations in brain structures involved in motivation, emotion, and decision making, including the medial prefrontal cortex, the nucleus accumbens, and the amygdala. We previously reported that induction of alcohol dependence was associated with long-term changes in the expression of genes involved in neurotransmitter release. Specifically, Syt1, which plays a key role in neurotransmitter release and neuronal functions, was downregulated. Here, we therefore examined the role of Syt1 in alcohol-associated behaviors in rats. METHODS: We evaluated the effect of Syt1 downregulation using an adeno-associated virus (AAV) containing a short hairpin RNA against Syt1. Cre-dependent Syt1 was also used in combination with an rAAV2 retro-Cre virus to assess circuit-specific effects of Syt1 knockdown (KD). RESULTS: Alcohol-induced downregulation of Syt1 is specific to the prelimbic cortex (PL), and KD of Syt1 in the PL resulted in escalated alcohol consumption, increased motivation to consume alcohol, and increased alcohol drinking despite negative consequences ("compulsivity"). Syt1 KD in the PL altered the excitation/inhibition balance in the basolateral amygdala, while the nucleus accumbens core was unaffected. Accordingly, a projection-specific Syt1 KD in the PL-basolateral amygdala projection was sufficient to increase compulsive alcohol drinking, while a KD of Syt1 restricted to PL-nucleus accumbens core projecting neurons had no effect on tested alcohol-related behaviors. CONCLUSIONS: Together, these data suggest that dysregulation of Syt1 is an important mechanism in long-term neuroadaptations observed after a history of alcohol dependence, and that Syt1 regulates alcohol-related behaviors in part by affecting a PL-basolateral amygdala brain circuit.

Compulsive alcohol drinking in rodents is associated with altered representations of behavioral control and seeking in dorsal medial prefrontal cortex

“…Therefore, we hypothesize that excitation of dmPFC excitatory neurons disrupted maladaptive processes necessary for the escalation of compulsive drinking. Indeed, recent research has shown that down regulation of SYT1 (a gene that influences synaptic transmission and plasticity) in prelimbic cortex increases compulsive alcohol consumption (assessed using quinine adulteration) and reduces neural excitability in Wistars with longer alcohol drinking histories 58 . Overall, while this and previous studies 21 , 22 have demonstrated that mPFC plays a functional role in compulsive drinking, this study also provided valuable insights into the neurocomputational phenomena underlying compulsive drinking.…”

An epigenetic mechanism for over-consolidation of fear memories

“…We used a dual vector approach, in which a retrogradely transported-AAV encoding Cre was injected into the BLA, and an AAV encoding Cre-dependent Prdm2 microRNA was infused into the dmPFC (Fig. 3A, B ) [ 42 ]. Similar to what we observed with a Prdm2 KD in dmPFC that was not projection-specific, Prdm2 KD in dmPFC-BLA projecting neurons did not affect the acquisition of conditioned fear (Fig.…”

Prelimbic neuron calcium activity predicts perceived hedonic value across drinking solutions and ethanol dependent states in mice

“…It is possible that ethanol dependence or a long history of excessive intake would produce an imbalance in excitation/inhibition processes that shift reward encoding toward ethanol over water in PrL→NAcore projections. Alternatively, other circuits, such as PrL→basolateral amygdala projections, might encode and drive excessive ethanol drinking in dependent mice (Barbier et al, 2021). In summary, monitoring population calcium activity in PrL cortex identified an intention signal that varied with the perceived hedonic value of different drinking solutions and tracked changes in compulsive-like ethanol drinking in dependent mice.…”

“…Prolonged up-states in PrL→NAcore projection neurons also differed from the overall population in that up-state characteristics were similar with and without drinking bouts, demonstrating that the PrL→NAcore projection is encoding different aspects of hedonic value favoring water over ethanol when given a choice. Perhaps these findings are not surprising given the known role for the PrL cortex in controlling cue-induced reinstatement (Keistler et al, 2017) and compulsive-like ethanol drinking (Seif et al, 2013;Barbier et al, 2021). It is possible that ethanol dependence or a long history of excessive intake would produce an imbalance in excitation/inhibition processes that shift reward encoding toward ethanol over water in PrL→NAcore projections.…”

“…Chronic exposure to ethanol in rodents produces functional (Kroener et al, 2012;Trantham-Davidson et al, 2014;Pleil et al, 2015b;Klenowski et al, 2016;Varodayan et al, 2018;Hughes et al, 2019;Hughes et al, 2020;Joffe et al, 2020Joffe et al, , 2021, molecular (Melendez et al, 2012;Barbier et al, 2017), and morphological (Kroener et al, 2012;Klenowski et al, 2016;Varodayan et al, 2018;Frost et al, 2019;Cannady et al, 2021) neuroadaptations in the PrL cortex. Importantly, these adaptations are proposed as critical drivers of behavioral deficits related to cognitive performance (Kroener et al, 2012;Hu et al, 2015) and compulsive ethanol drinking (Seif et al, 2013;Barbier et al, 2015;Barbier et al, 2017;Barbier et al, 2021). mPFC neurons can encode anticipatory and goal-directed drinking behaviors (Amiez et al, 2006;Petyko et al, 2009;Horst and Laubach, 2013;Jezzini et al, 2013;Parent et al, 2015;Amarante et al, 2017;Linsenbardt et al, 2019).…”