Gut, N. K. | Search bioRxiv

bioRxiv2022

Selective inhibition of goal-directed actions in the mesencephalic locomotor region

Dopamine enables purposive behavior and adjusts vigor as a function of the relative value of actions. In Parkinsons disease, dopamine neurons die and give rise to a series of motor and cognitive changes that interfere with the expression of volitional actions. Here we report a novel inhibitory input to dopamine neurons originated in the mesencephalic locomotor region that selectively blocks purposive behavior. GABAergic neurons of the pedunculopontine nucleus (PPN) synapse onto dopamine neurons of the substantia nigra and decrease dopamine release in the dorsal striatum. Activation of PPN neurons abolished exploratory locomotion and goal-directed actions while preserved other motor behaviors; furthermore, PPN caused a decrease in movement vigor and interrupted motor sequences presumably by modulating the immediate value of the learned action. Our results reveal an inhibitory mechanism in the midbrain that rapidly and reversibly adjusts the intrinsic value of ongoing actions.

neuroscience↗

bioRxiv2020

Whole-brain mapping of monosynaptic inputs to midbrain cholinergic neurons

The cholinergic midbrain is involved in a wide range of motor and cognitive processes. Cholinergic neurons of the pedunculopontine (PPN) and laterodorsal tegmental nucleus (LDT) send long-ranging axonal projections that target sensorimotor and limbic areas in the thalamus, the dopaminergic midbrain and the striatal complex following a topographical gradient, where they influence a range of functions including attention, reinforcement learning and action-selection. Nevertheless, a comprehensive examination of the afferents to PPN and LDT cholinergic neurons is still lacking, partly due to the neurochemical heterogeneity of this region. Here we characterize the whole-brain input connectome to cholinergic neurons across distinct functional domains (i.e. PPN vs LDT) using conditional transsynaptic retrograde labeling in ChAT::Cre male and female rats. The quantification of input neurons revealed that both PPN and LDT receive similar substantial inputs from the superior colliculus and the output of the basal ganglia (i.e. substantia nigra pars reticulata). In addition, we found that PPN cholinergic neurons receive preferential inputs from basal ganglia structures than from the cortex, whereas LDT cholinergic neurons receive preferential inputs from cortical areas. Our results provide the first characterization of inputs to PPN and LDT cholinergic neurons. The differences in afferents to each cholinergic structure support their differential roles in behavior. Significance statementAcetylcholine is a widespread neuromodulator that regulates a wide variety of functions including learning, goal-directed behavior and execution of movements. In this study we characterized the distribution of presynaptic neurons that modulate the activity of functionally distinct midbrain cholinergic neurons located in the pedunculopontine nucleus (PPN) and the laterodorsal tegmental nucleus (LDT) by using a transsynaptic, modified-rabies virus strategy. We reveal that input neurons are widely distributed throughout the brain but segregated into specific functional domains. Motor related areas innervate preferentially the PPN, whereas limbic related areas preferentially innervate the LDT. Our results suggest that input neurons located along distinct functional domains have differential impact over cholinergic midbrain regions.

neuroscience↗