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

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.

Grant Number: 5I01BX005984-04
NIH Institute/Center: VA
Principal Investigator: Erik Carlson