Dopaminergic systems have been known to be involved in the regulation of locomotor activity and development of psychosis. However, the observations that some Parkinson's disease patients can move effectively under appropriate conditions despite low dopamine levels (eg, kinesia paradoxia) and that several psychotic symptoms are typical antipsychotic resistant and atypical antipsychotic sensitive indicate that other systems beyond the dopaminergic system may also affect locomotor activity and psychosis. The present study showed that dopamine-deficient (DD) mice, which had received daily L-DOPA injections, could move effectively and even be hyperactive 72 h after the last L-DOPA injection when dopamine was almost completely depleted. Such hyperactivity was ameliorated by clozapine but not haloperidol or ziprasidone. Among multiple actions of clozapine, muscarinic acetylcholine (ACh) activation markedly reduced locomotor activity in DD mice. Furthermore, the expression of choline acetyltransferase, an ACh synthase, was reduced and extracellular ACh levels were significantly reduced in DD mice. These results suggest that the cholinergic system, in addition to the dopaminergic system, may be involved in motor control, including hyperactivity and psychosis. The present findings provide additional evidence that the cholinergic system may be targeted for the treatment of Parkinson's disease and psychosis.

The cerebellum regulates complex animal behaviors, such as motor control and spatial recognition, through communication with many other brain regions. The major targets of the cerebellar projections are the thalamic regions including the ventroanterior nucleus (VA) and ventrolateral nucleus (VL). Another thalamic target is the central lateral nucleus (CL), which receives the innervations mainly from the dentate nucleus (DN) in the cerebellum. Although previous electrophysiological studies suggest the role of the CL as the relay of cerebellar functions, the kinds of behavioral functions mediated by cerebellothalamic tracts projecting to the CL remain unknown. Here, we used immunotoxin (IT) targeting technology combined with a neuron-specific retrograde labeling technique, and selectively eliminated the cerebellothalamic tracts of mice. We confirmed that the number of neurons in the DN was selectively decreased by the IT treatment. These IT-treated mice showed normal overground locomotion with no ataxic behavior. However, elimination of these neurons impaired motor coordination in the rotarod test and forelimb movement in the reaching test. These mice showed intact acquisition and flexible change of spatial information processing in the place discrimination, Morris water maze, and T-maze tests. Although the tract labeling indicated the existence of axonal collaterals of the DN-CL pathway to the rostral part of the VA/VL complex, excitatory lesion of the rostral VA/VL did not show any significant alterations in motor coordination or forelimb reaching, suggesting no requirement of axonal branches connecting to the VL/VA complex for motor skill function. Taken together, our data highlight that the cerebellothalamic tracts projecting to the CL play a key role in the control of motor skills, including motor coordination and forelimb reaching, but not spatial recognition and its flexibility.

Flexible switching of behaviours depends on integrative functioning through the neural circuit connecting the prefrontal cortex and the dorsomedial striatum (DMS). Although cholinergic interneurons modulate striatal outputs by diverse synaptic mechanisms, the roles of cholinergic interneurons in the DMS appear to vary among different models used to validate behavioural flexibility. Here, we conducted immunotoxin-mediated cell targeting of DMS cholinergic interneurons and examined the functions of these interneurons in behavioural flexibility, with the learning conditions differing in trial spacing and discrimination type in a modified T-maze. Elimination of the DMS cholinergic cell group normally spared reversal learning in place discrimination with an intertrial interval (ITI) of 15 s, but it impaired the reversal performance in response discrimination with the same ITI. In contrast, DMS cholinergic elimination resulted in enhanced reversal performance in both place and response discrimination tasks with a 10-min ITI and accelerated the reversal of response discrimination with a 20-min ITI. Our previous study also showed an enhanced influence of cholinergic targeting on place reversal learning with a 20-min ITI, and the present results demonstrate that DMS cholinergic interneurons act to inhibit both place and response reversal performance with a relatively longer ITI, whereas their functions differ between types of reversal performance in the tasks with a shorter ITI. These findings suggest distinct roles of the DMS cholinergic cell group in behavioural flexibility dependent on the trial spacing and discrimination type constituting the learning tasks.

The increasing prevalence of obesity and its effects on our society warrant intensifying basic animal research for understanding why habitual intake of highly palatable foods has increased due to recent global environmental changes. Here, we report that pregnant mice that consume a diet high in omega-6 (n-6) polyunsaturated fatty acids (PUFAs) and low in omega-3 (n-3) PUFAs (an n-6 high /n-3 low diet), whose n-6/n-3 ratio is approximately 120, induces hedonic consumption in the offspring by upregulating the midbrain dopaminergic system. We found that exposure to the n-6 high /n-3 low diet specifically increases the consumption of palatable foods via increased mesolimbic dopamine release. In addition, neurodevelopmental analyses revealed that this induced hedonic consumption is programmed during embryogenesis, as dopaminergic neurogenesis is increased during in utero access to the n-6 high /n-3 low diet. Our findings reveal that maternal consumption of PUFAs can have long-lasting effects on the offspring's pattern for consuming highly palatable foods.