Probes for INS

The experience of coupling between motor output and visual feedback is necessary for the development of visuomotor skills and shapes visuomotor integration in visual cortex. Whether these experience-dependent changes of responses in V1 depend on modifications of the local circuit or are the consequence of circuit changes outside of V1 remains unclear. Here, we probed the role of N-methyl-d-aspartate (NMDA) receptor-dependent signaling, which is known to be involved in neuronal plasticity, in mouse primary visual cortex (V1) during visuomotor development. We used a local knockout of NMDA receptors and a photoactivatable inhibition of CaMKII in V1 during the first visual experience to probe for changes in neuronal activity in V1 as well as the influence on performance in a visuomotor task. We found that a knockout of NMDA receptors before, but not after, first visuomotor experience reduced responses to unpredictable stimuli, diminished the suppression of predictable feedback in V1, and impaired visuomotor skill learning later in life. Our results demonstrate that NMDA receptor-dependent signaling in V1 is critical during the first visuomotor experience for shaping visuomotor integration and enabling visuomotor skill learning.

Synaptotagmin 7 (Syt7) is a high-affinity calcium sensor that is implicated in multiple aspects of synaptic transmission. Here, we study the influence of Syt7 on the climbing fiber (CF) to Purkinje cell (PC) synapse. We find that small facilitation and prominent calcium-dependent recovery from depression at this synapse do not rely on Syt7 and that Syt7 is not normally present in CFs. We expressed Syt7 in CFs to assess the consequences of introducing Syt7 to a synapse that normally lacks Syt7. Syt7 expression does not promote asynchronous release or accelerate recovery from depression. Syt7 decreases the excitatory postsynaptic current (EPSC) magnitude, consistent with a decrease in the initial probability of release (PR). Syt7 also increases synaptic facilitation to such a large extent that it could not arise solely as an indirect consequence of decreased PR. Thus, the primary consequence of Syt7 expression in CFs, which normally lack Syt7, is to promote synaptic facilitation.

Melanin-concentrating hormone (MCH) is an orexigenic neuropeptide that acts through its receptor (MCHR1) to promote positive energy balance by increasing food intake and decreasing energy expenditure. MCH has been shown to inhibit dopamine release from the mesocorticolimbic dopamine pathway originating in the ventral tegmental area (VTA), and a hyperdopaminergic state underlies hyperactivity observed in animals lacking MCH or MCHR1. However, it is not known if the inhibitory effect of MCH on dopaminergic tone could be due to direct regulation of dopaminergic VTA neurons. We used a combination of molecular, neuroanatomical, and electrophysiological techniques to assess MCHR1 expression and activation in the VTA. MCH neurons project to the VTA, which comprises nerve terminals that contain MCH and may represent MCH release sites. Consistent with this, we detected MCHR1 expression on major VTA cell types, including those that are dopaminergic, GABAergic, and glutamatergic. Functional MCHR1 activation may regulate dopamine release via two mechanisms, one by acutely and directly inhibiting dopaminergic VTA neurons, and the other by disinhibiting glutamatergic afferents to dopaminergic VTA neurons. While we have not measured dopamine release in this present thesis, we postulate that MCH may acutely suppress dopamine release, while concurrently engaging local glutamatergic signaling to restore dopamine levels. These results signify that the VTA is a novel target for MCH-mediated physiology, including for the maintenance of energy homeostasis

Exposure to irregular lighting schedules leads to deficits in affective behaviors. The retino-recipient perihabenular nucleus (PHb) of the dorsal thalamus has been shown to mediate these effects in mice. However, the mechanisms of how light information is processed within the PHb remains unknown. Here, we show that the PHb contains a distinct cluster of GABAergic neurons that receive direct retinal input. These neurons are part of a larger inhibitory network composed of the thalamic reticular nucleus and zona incerta, known to modulate thalamocortical communication. In addition, PHbGABA neurons locally modulate excitatory-relay neurons, which project to limbic centers. Chronic exposure to irregular light-dark cycles alters photo-responsiveness and synaptic output of PHbGABA neurons, disrupting daily oscillations of genes associated with inhibitory and excitatory PHb signaling. Consequently, selective and chronic PHbGABA manipulation results in mood alterations that mimic those caused by irregular light exposure. Together, light-mediated disruption of PHb inhibitory networks underlies mood deficits.

Extracting the valence of environmental cues is critical for animals' survival. How valence in sensory signals is encoded and transformed to produce distinct behavioral responses remains not well understood. Here, we report that the mouse pontine central gray (PCG) contributes to encoding both negative and positive valences. PCG glutamatergic neurons were activated selectively by aversive, but not reward, stimuli, whereas its GABAergic neurons were preferentially activated by reward signals. The optogenetic activation of these two populations resulted in avoidance and preference behavior, respectively, and was sufficient to induce conditioned place aversion/preference. Suppression of them reduced sensory-induced aversive and appetitive behaviors, respectively. These two functionally opponent populations, receiving a broad range of inputs from overlapping yet distinct sources, broadcast valence-specific information to a distributed brain network with distinguishable downstream effectors. Thus, PCG serves as a critical hub to process positive and negative valences of incoming sensory signals and drive valence-specific behaviors with distinct circuits.