Biology subjects

Becchi, S.

Publications and source records attributed to Becchi, S..

3 recordsLinked to original sources

bioRxiv2022

CRF receptor type 1 modulates the nigrostriatal dopamine projection and facilitates cognitive flexibility after acute and chronic stress

Chronic unpredictable stress (CUS) impairs cognitive flexibility in rats, particularly when faced with additional mild acute stress (AS). We tested the hypothesis that this impairment is associated with alterations in dopamine activity in the dorsal striatum driven by corticotropin-releasing-factor receptor type 1 (CRFR1) in the substantia nigra pars compacta (SNpc). In experiment 1, rats received CUS or handling for 14 days, before learning two action-outcome associations (lever presses and food rewards). Learning was assessed using outcome devaluation. Cognitive flexibility was then assessed by reversing the outcome identities followed by a second outcome devaluation test, with half of the rats in each group receiving AS prior to reversal training. Dopamine and its metabolite were quantified in the dorsal striatum and CRFR1 mRNA was quantified in the SNpc. Increased dopaminergic activity in the left dorsal striatum and CRFR1 expression in the left SNpc were associated with resilience to AS in naive rats but with impairment in CUS+AS rats, suggesting a transition in hemispheric control from left to right as a protective mechanism following CUS. This suggestion was tested in experiment 2, where SNpc CRFR1 was blocked unilaterally prior to AS and reversal training. Blocking CRFR1 in the left medial SNpc impaired cognitive flexibility following AS in naive rats but restored it in CUS rats. Blocking CRFR1 in the left, but not right, lateral SNpc also impaired cognitive flexibility following AS in naive rats but had no effect in CUS rats.

neuroscience↗

bioRxiv2022

Cognitive effects of thalamostriatal degeneration are ameliorated by normalizing striatal cholinergic activity

The loss of neurons in parafascicular thalamus (Pf) and of their inputs to dorsomedial striatum (DMS) are associated with Lewy body disease (LBD) and Parkinsons disease dementia (PDD) and have been linked to the effects of neuroinflammation. In rats, these inputs regulate the function of striatal cholinergic interneurons (CINs) that are necessary for the flexible encoding of the action-outcome (AO) associations for goal-directed action. We found that these inputs modify the encoding, not retrieval, of new AO associations and cause burst-pause firing of CINs in the DMS during AO remapping. These adaptive effects were abolished by neuroinflammation in the Pf, resulting in the loss of goal-directed control when the rats were required to update AO associations after a change in contingency. We found that the neuronal and behavioral deficits induced by inflammation in the Pf were rescued by administration of selegiline, a MAO-B inhibitor that we found also enhances ATPase activity in CINs, suggesting a potential treatment for cognitive deficits associated with inflammation affecting the function of midline thalamic nuclei and related structures.

neuroscience↗

bioRxiv2022

Goal-directed action is transiently impaired in an hAPP-J20 mouse model of Alzheimer's disease, and in aging male mice regardless of genotype

Cognitive-behavioural testing in preclinical models of Alzheimers disease has typically been limited to visuo-spatial memory tests and has failed to capture the broad scope of deficits patients also display in goal-directed action control. The current study addresses this gap by providing the first comprehensive investigation of how goal-directed actions are affected in a transgenic mouse model of Alzheimers disease. Specifically, we tested outcome devaluation performance - a popular test of goal-directed action - in male and female human amyloid precursor protein (hAPP)-J20 mice. Mice were first trained to press a left and right lever for unique pellet and sucrose outcomes respectively (counterbalanced) over four days. On test, mice were fed one of the two outcomes to reduce its value via sensory specific satiety and subsequently given a choice between levers. Goal-directed action was intact for 36-week-old wildtype mice of both sexes, because they responded more on the lever associated with the still-valued outcome than that associated with the devalued outcome (i.e. Valued > Devalued). Goal-directed action was impaired (Valued = Devalued) for J20 mice of both sexes, and for 52-week-old male mice regardless of genotype. Following an additional 4 days of lever press training (i.e., 8 days lever pressing in total), outcome devaluation was intact for all mice regardless of age or genotype. Immunohistochemical analysis revealed that increased microglial expression in the dorsal CA1 region of the hippocampus was associated with poorer outcome devaluation performance on initial tests, but not with tests performed after 8 days of lever pressing. Together, these data demonstrate that goal-directed action is transiently impaired in J20 mice of both sexes and in aging male mice regardless of genotype, and that this impairment is related to neuroinflammation in the dorsal CA1 region of the hippocampus.

animal behavior and cognition↗