Cerebellar Modulation of Mesolimbic Dopamine Transmission is Functionally Asymmetrical

Abstract

Cerebral and cerebellar hemispheres are known to be asymmetrical in structure and function, and previous literature supports that asymmetry extends to the neural dopamine systems. Using in vivo fixed-potential amperometry with carbon-fiber microelectrodes in anesthetized mice, the current study assessed hemispheric lateralization of stimulation-evoked dopamine in the nucleus accumbens (NAc) and the influence of the cerebellum in regulating this reward-associated pathway. Our results suggest that cerebellar output can modulate mesolimbic dopamine transmission, and this modulation contributes to asymmetrically lateralized dopamine release. Dopamine release did not differ between hemispheres when evoked by medial forebrain bundle (MFB) stimulation; however, dopamine release was significantly greater in the right NAc relative to the left when evoked by electrical stimulation of the cerebellar dentate nucleus (DN). Furthermore, cross-hemispheric talk between the left and right cerebellar DN does not seem to influence mesolimbic release given that lidocaine infused into the DN opposite to the stimulated DN did not alter release. These studies may provide a neurochemical mechanism for studies identifying the cerebellum as a relevant node for reward, motivational behavior, saliency, and inhibitory control. An increased understanding of the lateralization of dopaminergic systems may reveal novel targets for pharmacological interventions in neuropathology of the cerebellum and extending projections. (PPT), which projects to and stimulates dopamine cell bodies in the VTA [46,47]. For this reason, the present study stimulated the DN located contralateral to the NAc recording site (left DN stimulation with right NAc recording and vice versa). Lastly, in Experiment 3, we examined the potential cross-hemispheric influence of cerebellar DN on this dopaminergic pathway. During contralateral DN stimulation-evoked dopamine recordings, separate groups of mice received an infusion of either lidocaine or phosphate-buffered saline (PBS; vehicle control) into the ipsilateral DN to determine if communication between each cerebellar DN can influence the contralateral, active pathway being stimulated. (See Figure 1 for a depiction of the experimental configurations.) These experiments are the first to systematically examine the contribution of the cerebellum on lateralized stimulation-evoked phasic dopamine release in the NAc. An improved understanding of cerebello-cortico circuitry may help identify targets for pharmacological interventions in neuropathologies related to dopamine dysfunction.

Systemic Ghrelin Treatment Induces Rapid, Transient, and Asymmetric Changes in the Metabolic Activity of the Mouse Brain

“…Importantly, the asymmetric effects of ghrelin on the metabolic brain activity may result from the inherent lateralization of some brain functions [81]. For instance, the mesolimbic system in rats shows inherent functional lateralization as indicated by the observations that the right cortex and nucleus accumbens contain higher basal levels of DA, as compared to the left structures, and that the right nucleus accumbens receives greater dopaminergic neurotransmission, as compared to the left nucleus accumbens, in response to cerebellar stimulation [82,83]. Also, some limbic centers in rats display unilateral 18 F-FDG uptake in response to the systemic administration of an opioid receptor agonist [84].…”

Cerebellar Activation Bidirectionally Regulates Nucleus Accumbens Core and Medial Shell

“…To examine functional connectivity between CB and NAc, we recorded ongoing spiking activity from NAcMed and NAcCore in vivo and electrically microstimulated the DCN ( Figure 1A,B). We primarily targeted the lateral DCN, activation of which has been shown to modulate levels of dopamine in NAc 53 . In a subset of experiments, post-hoc analysis localized the bipolar stimulating electrode in the interposed DCN, and these data were included in our analysis.…”

“…Here, we focused on the nucleus accumbens (NAc), a complex limbic structure that shares reward, motivation and affective functionality with the CB 49,50 . Stimulation of CB cortex or deep cerebellar nuclei (DCN) modulates levels of NAc dopamine-an important, but not exclusive, regulator of NAc functions [51][52][53][54][55][56][57] . However, how the CB connects to NAc is unknown.…”

Inhibition of androgenic pathway impairs encoding of cerebellar‐dependent motor learning in male rats

“…Moreover, androgens could more widely impact motor and nonmotor functions via influencing the cerebellum. The cerebellum, indeed, communicates with the brainstem and with various circuitry in cerebral cortical areas that play a central role in many aspects of cognition and movement (Holloway et al., 2019; Ito, 2006; Salmi et al., 2010; Schmahmann, 2001; Sokolov et al., 2014; Strick et al., 2009; Xue et al., 2021).…”