Recruitment of Cerebellar Circuits to Modulate Cognition, Reward and Avoidance of Threat

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Studies in humans and non-human primates have identified a region of the dentate nucleus of the cerebellum (DCN), or lateral nucleus in rodents (LCN), which is activated during performance of complex cognitive tasks. We have previously shown that the dopamine D1 receptor and the vesicular glutamate transporter-2 (Vglut2) mark different populations of neurons in the LCN and modulate cognitive performance on tasks related to attention and working memory. The DCN is implicated in cognitive function in humans with psychiatric illnesses, but virtually nothing is known about its basic anatomical and functional organization. Unraveling this will set the stage for precision therapeutics in the cognitive domain, an area where we have few options to offer Veterans with psychiatric disorders. Veterans with PTSD and TBI, for example, show neuroanatomical and clinical markers of cerebellar dysfunction which correlate with the severity of cognitive and PTSD symptoms. Aberrant dopamine signaling arising from the ventral tegmental area (VTA) is also a likely contributor to dysfunction in PTSD, and it has been repeatedly shown by our group and others that cerebellar nuclei have inputs to the ventral tegmental area, a brain region at the heart of the mesolimbic dopamine system which mediates reward and fear learning. VTA and cerebellar circuits (LCN and posterolateral cerebellar cortex) are strongly implicated in the sensation and production of prediction errors (reward/threat and sensory errors, respectively) for cognitive and emotional function. Humans with discrete cerebellar lesions manifest neuropsychiatric symptoms, including depression, reduced language and social interactions, impaired interval timing, disturbances of working memory, spatial cognition, and attention in the absence of motor deficits. When we have experimentally perturbed catecholaminergic inputs to the LCN in mice, we have found impairments in behavioral flexibility, response inhibition, social recognition memory, and associative fear learning relative to controls, but no deficits in gross motor, sensory, instrumental learning, or sensorimotor gating functions. We hypothesize that one source of aberrant cognitive function in psychiatric disorder stems from faulty circuitry between the well-characterized VTA and the understudied cerebellum. Notably, cerebellar activations seen in Parkinson’s Disease, after recovery from stroke in humans, and experimental animal models of hemispherectomy demonstrate the necessity of cerebellum in recovery. Whether these cerebellar mechanisms are active in the etiology of cognitive dysfunction, or whether they can be recruited by an intervention during recovery is unknown. It is well known that following associative or reinforcement learning, the VTA dopamine signal shifts to a cue which predicts a reward or threat. When conditioned stimuli (CS+) are presented and rewards are omitted, dopamine neurons in the VTA display prediction errors. The overarching hypothesis of this grant is that the cerebellum facilitates this type of learning, and that circuit dysfunction between the LCN and VTA may be a critical component of different psychiatric disorders. We will use mice with a targeted mutation of Vglut2 in combination with specific viral, optogenetic, in vivo electrophysiology and fiber photometry approaches to characterize and manipulate the activity of specific LCN Neurons projecting to VTA. Leveraging these cutting-edge tools paired with classical behavioral assays will offer insights into this circuit, which holds promise as a target of intervention with neuromodulatory, behavioral, or pharmacological approaches.