Voluntary alcohol consumption disrupts coupling of prefrontal cortical activity to arousal

Abstract

Alcohol use disorder (AUD) exacts a major personal, societal, and economic toll. Top-down control from the prefrontal cortex (PFC), a critical hub for decision making, executive, and other cognitive functions, is key for the regulation of alcohol consumption. Arousal exerts profound effects on cortical processing, allowing it to potentially modulate PFC functions relevant for alcohol consumption and AUD. Despite this, it is unclear whether and how arousal-mediated modulation of PFC circuits relates to voluntary alcohol drinking behaviors. Two-photon microscopy is ideally suited for dissecting the neural circuit mechanisms underlying the effect of alcohol on intact circuits in behaving animals. We addressed a major limitation of this technology by developing a novel behavioral paradigm for voluntary drinking in head-fixed mice. We recorded responses of layer 2/3 excitatory neurons in the anterior cingulate cortex (ACC) subdivision of the PFC as mice voluntarily consumed ethanol, along with video recording of the pupil to track momentary fluctuations in arousal. Ethanol consumption bidirectionally modified the activity of subsets of ACC neurons, both at slow (minutes) and fast (sub-second) time scales. Remarkably, we found that the coupling of arousal to ACC activity before drinking was associated with subsequent ethanol engagement behavior. In turn, ethanol consumption modulated neuronal-arousal coupling. Together, our results suggest neuronal-arousal coupling as a key biomarker for alcohol drinking and lays the groundwork for future studies to dissect the therapeutic potential of this process for AUD and other substance use disorders.

Multicore fiber optic imaging reveals that astrocyte calcium activity in the mouse cerebral cortex is modulated by internal motivational state

“…Mice were induced to walk on a motorized treadmill (scheme, Fig. 1e), a condition known to elicit a global rise in calcium within cortical astrocytes due to the local release of norepinephrine (NE) that accompanies enhanced arousal 27,40,44 . Astrocytes throughout the imaging field in astro-GC3 mice exhibited transient increases in fluorescence (Fig.…”

Structured tracking of alcohol reinforcement (STAR) for basic and translational alcohol research

“…However, as clinical goals shift towards personalized medication strategies, there is increasing need for preclinical models of alcohol use that capture individual differences and incorporate multimodal assessments of specific behaviors within the AUD spectrum [52,53]. At the same time, advances in neurotechnologies for interrogating in vivo cellular activity in real-time have rapidly transformed behavioral neurosciences but are often incompatible with established AUD models, resulting in a divergence of methodologies throughout the field [43,76,77]. Here, to address these issues, we establish an approach for Structured Tracking of Alcohol Reinforcement.…”

Non-Consummatory Behavior Signals Predict Aversion-Resistant Alcohol Drinking in Head-Fixed Mice

“…Despite the advantages of these head-fixed techniques, as well as extensive research on alcohol consumption and ARD using quinine in freely moving mice, very little data exist regarding alcohol consumption and ARD in head-fixed mice. To date, it has been shown that head-fixed mice will voluntarily consume alcohol [46], but no studies have documented ARD using quinine in head-fixed mice. Furthermore, no studies have related head-fixed alcohol drinking and ARD to home-cage drinking patterns and ARD.…”

“…For instance, these techniques make it possible to record from large portions of the cortical surface using widefield calcium imaging [42], to simultaneously record from and manipulate brain region level populations with two-photon calcium imaging and optogenetics [43], or record from thousands of neurons simultaneously across multiple brain regions using multiple high-density electrophysiology probes [44]. Furthermore, due to the stable positioning of the animal, these methods facilitate motion tracking of individual body parts [45] and advanced behavioral analyses [46][47][48][49][50][51][52][53][54][55], as well as the precise delivery of visual [56], auditory [57], and olfactory stimuli [58,59]. This improved precision reduces noise between behavioral data, stimuli, and neural activity in comparison to freely moving mice.…”

“…Head-fixed mouse preparations offer the potential to meet this need because these methods allow researchers to exploit powerful neural recording techniques, such as calcium imaging [31,32] and high-yield, multi-brain region electrophysiology [33,34]. Furthermore, due to the stable positioning of the animal, these methods facilitate motion tracking of individual body parts [35] and advanced behavioral analyses [36][37][38][39][40][41][42][43][44][45]. Head-fixed methods have been widely utilized in various types of non-addiction related studies [46][47][48].…”