Recruitment of Cerebellar Circuits with Balance Training for Cognitive Rehabilitation in a Mouse Model of Mild Traumatic Brain Injury

Declines in cognitive and balance function are associated with numerous neuropsychiatric disorders affecting
Veterans, including post-traumatic stress disorder (PTSD) and traumatic brain injury (TBI). Both functions have
overlap, in the form of functional activation, in the human cerebellum. TBI exposure is particularly relevant to
Veterans and increases risk of cognitive dysfunction, disequilibrium and imbalance, and dementia. TBI is the
signature injury of the wars in Iraq and Afghanistan and increases risk of both cognitive dysfunction and
dementia. Across these disorders, these symptoms have a paucity of treatments. The burden of TBI on
families and the US health system is enormous, so novel interventions are of great interest. Treatments that
elicit improved balance in the young and elderly also improve cognitive symptoms. 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 cognitive tasks involving complex spatial and
sequential planning. Posterior-lateral areas of the human cerebellum that are associated with cognitive
function, grip strength, and gait speed overlap and project to the DCN. This locus in the brain is particularly
promising, as there is evidence that the cerebellum ages more slowly than the rest of the brain and shows
compensatory activation in stroke and neurodegenerative disease. We have previously begun to dissect the
circuit components of this nucleus in mice and defined a role for specific LCN circuits in supporting cognitive
functions in working memory, episodic memory, response inhibition, sensory discrimination, and social
functions. We have also shown that this region directly wires to midbrain structures, such as the ventral
tegmental area, involved in associative learning. In preliminary data, we show that a specific rotarod-based
balance training protocol rescues several cognitive and affective symptoms, particularly with respect to
associative learning in both reward learning and response to threat stimuli, in a mild TBI (mTBI) mouse model
relevant to mTBI and PTSD in Veterans. In this grant proposal, we will behaviorally dissect specific
contributions of exercise versus balance in this mTBI model and determine their effects on cognitive function.
In other words, we will quantify levels of response inhibition and impulsivity, spatial navigation memory, and
incubation of fear in mTBI mice treated with different balance and exercise interventions designed to isolate
effects of balance training from exercise. This grant also aims to determine whether rotarod-based balance
training 1) alter the subpopulations of neuroinflammatory cells called microglia so that they are more
neuroprotective rather than neurotoxic, and 2) it can recruit a specific cognitive cerebellar circuit in the LCN. To
accomplish this, we will use immunohistochemistry, protein quantification methods and single cell RNA
Sequencing of microglia from the LCN. We will also use a chemogenetic circuit approach (inhibitory and
excitatory DREADDs) to increase or decrease the excitability of a specific excitatory output population of cells
in the lateral (dentate) nucleus of the cerebellum during balance training. Then, we will test the functional
outcomes of these perturbations in the above tests of response inhibition and impulsivity, spatial navigation
memory, and incubation of fear. Successful completion of our proposed aims will provide novel insight into a
preclinical model of balance training in mice, circuits in the cerebellum that support cognitive and equilibrium
functions, and establish a framework for novel, precision therapeutics to assist patients with TBI or
neurodegenerative disease with cognitive and equilibrium dysfunction.

Grant Number: 5I01RX003829-03
NIH Institute/Center: VA
Principal Investigator: Erik Carlson