Tsc1-mTOR signaling controls the structure and function of midbrain dopamine neurons

Abstract

mTOR complex 1 (mTORC1) is a central coordinator of cell growth and metabolism. Mutations in regulators of mTORC1 cause syndromic disorders with a high prevalence of cognitive and psychiatric conditions. To elucidate the cellular origins of these manifestations, we conditionally deleted the gene encoding the mTORC1 negative regulator Tsc1 from mouse midbrain dopamine neurons, which modulate motor, affective, and cognitive behaviors that are frequently affected in psychiatric disorders. Loss of Tsc1 and constitutive activation of mTORC1 strongly impacted the properties of dopamine neurons, causing somatodendritic hypertrophy, reduced intrinsic excitability, altered axon terminal ultrastructure, and severely impaired dopamine release. These perturbations were associated with selective deficits in cognitive flexibility, which could be prevented by genetic reduction of the obligatory mTORC1 protein Raptor. Our results establish a critical role for mTORC1 in setting the functional properties of midbrain dopamine neurons, and indicate that dopaminergic dysfunction may underlie cognitive inflexibility in mTOR-related syndromes.

Transient food insecurity during the juvenile-adolescent period affects adult weight, cognitive flexibility, and dopamine neurobiology

“…In our study, we found differences in neurobiology that could plausibly cause the different behavioral phenotypes, 38,60 but we did not test this connection with further manipulations or in vivo measurement. In addition, we only took neurobiological measures from adult male mice.…”

“…These data are in line with findings in human literature that females are at higher risk to develop obesity with FI experience. [32][33][34] In male mice, feeding history affected reversal learning in adulthood We next used a 4-choice odor-based foraging (4COF) task [35][36][37][38] (Figure 2A) to test how juvenile-adolescent feeding history affected capacity for learning and cognitive flexibility in adulthood. The mice were tested in discrimination and reversal learning phases in which a reward was obtained by digging selectively in one of four pots with different scented shavings.…”

“…58,59 In addition, two studies that manipulated activity and signaling of dopamine neurons and used the same 4COF task in adult animals also found effects on cognitive flexibility in reversal phase. 38,60 We posit that complex interplay of differences in firing patterns, and intracellular signaling on the timescales of seconds to minutes, as well as hours and days, could lead to functional differences in dopamine neurons and cortico-striatal circuits, that result in behavioral differences in flexible updating in the tasks (see Lin et al for a working model 22 ).…”

“…72 Fast scan cyclic voltammetry (FSCV) Dopamine release was monitored using FSCV in acute coronal slices containing striatum. 38,73 Separate cohorts of male AL and FI mice at P61-70 were anesthetized with isoflurane and decapitated. Following decapitation, the brain was removed.…”