Cell-Type-Specific Control of Brainstem Locomotor Circuits by Basal Ganglia.

The basal ganglia (BG) are critical for adaptive motor control, but the circuit principles underlying their pathway-specific modulation of target regions are not well understood. Here, we dissect the mechanisms underlying BG direct and indirect pathway-mediated control of the mesencephalic locomotor region (MLR), a brainstem target of BG that is critical for locomotion. We optogenetically dissect the locomotor function of the three neurochemically distinct cell types within the MLR: glutamatergic, GABAergic, and cholinergic neurons. We find that the glutamatergic subpopulation encodes locomotor state and speed, is necessary and sufficient for locomotion, and is selectively innervated by BG. We further show activation and suppression, respectively, of MLR glutamatergic neurons by direct and indirect pathways, which is required for bidirectional control of locomotion by BG circuits. These findings provide a fundamental understanding of how BG can initiate or suppress a motor program through cell-type-specific regulation of neurons linked to specific actions.

HTR2 receptors in a songbird premotor cortical-like area modulate spectral characteristics of zebra finch song.

Serotonin [5-hydroxytryptamine (5-HT)] is involved in modulating an array of complex behaviors including learning, depression, and circadian rhythms. Additionally, HTR2 receptors on layer V pyramidal neurons are thought to mediate the actions of psychedelic drugs; the native function of these receptors at this site, however, remains unknown. Previously, we found that activation of HTR2 receptors in the zebra finch forebrain song premotor structure the robust nucleus of the arcopallium (RA) led to increased excitation, and that endogenous 5-HT could roughly double spontaneous firing rate. Here, using in vivo single-unit recordings, we found that direct application of 5-HT to these same RA projection neurons, which are analogous to layer V cortical pyramidal neurons, caused a significant increase in the number of action potentials per song-related burst, and a dramatic decrease in signal-to-noise ratio. Injection of the serotonergic neurotoxin 5,7-dihydroxytryptamine into the third ventricle greatly reduced telencephalic 5-HT and resulted in decreased fundamental frequency of harmonic syllables as well as increased goodness of pitch. Both of these results can be explained by the observed actions of 5-HT on RA projection neurons, and both effects recovered to baseline within 2 weeks following the toxin injection. These results show that 5-HT is involved in modulating spectral properties of song, likely via effects on RA projection neurons, but that adult zebra finches can partially compensate for this deficit within 7 d.

Motor thalamus supports striatum-driven reinforcement.

Reinforcement has long been thought to require striatal synaptic plasticity. Indeed, direct striatal manipulations such as self-stimulation of direct-pathway projection neurons (dMSNs) are sufficient to induce reinforcement within minutes. However, it's unclear what role, if any, is played by downstream circuitry. Here, we used dMSN self-stimulation in mice as a model for striatum-driven reinforcement and mapped the underlying circuitry across multiple basal ganglia nuclei and output targets. We found that mimicking the effects of dMSN activation on downstream circuitry, through optogenetic suppression of basal ganglia output nucleus substantia nigra reticulata (SNr) or activation of SNr targets in the brainstem or thalamus, was also sufficient to drive rapid reinforcement. Remarkably, silencing motor thalamus-but not other selected targets of SNr-was the only manipulation that reduced dMSN-driven reinforcement. Together, these results point to an unexpected role for basal ganglia output to motor thalamus in striatum-driven reinforcement.

A daily oscillation in the fundamental frequency and amplitude of harmonic syllables of zebra finch song.

Complex motor skills are more difficult to perform at certain points in the day (for example, shortly after waking), but the daily trajectory of motor-skill error is more difficult to predict. By undertaking a quantitative analysis of the fundamental frequency (FF) and amplitude of hundreds of zebra finch syllables per animal per day, we find that zebra finch song follows a previously undescribed daily oscillation. The FF and amplitude of harmonic syllables rises across the morning, reaching a peak near mid-day, and then falls again in the late afternoon until sleep. This oscillation, although somewhat variable, is consistent across days and across animals and does not require serotonin, as animals with serotonergic lesions maintained daily oscillations. We hypothesize that this oscillation is driven by underlying physiological factors which could be shared with other taxa. Song production in zebra finches is a model system for studying complex learned behavior because of the ease of gathering comprehensive behavioral data and the tractability of the underlying neural circuitry. The daily oscillation that we describe promises to reveal new insights into how time of day affects the ability to accomplish a variety of complex learned motor skills.