Neurons interact in networks distributed throughout the brain. While much effort has focused on whole-brain calcium imaging, advances in genetically encoded voltage indicators raise the question of whether it might be possible to image neuronal voltage across entire brains. Achieving this requires a microscope with high volumetric imaging rates and signal-to-noise ratio. Here we present a remote-scanning light-sheet microscope capable of imaging genetically encoded voltage indicator-expressing neurons distributed throughout much of the brain of larval zebrafish at a volumetric rate of 200.8 Hz. We measured voltage traces from approximately one-quarter of all brain neurons. We found that neurons firing at different times during a sequence occupied different locations: visually evoked sequences mapped across the optic tectum, whereas stimulus-independent bursts were mapped across the cerebellum and medulla. Imaging voltage of neurons distributed in many brain regions may open new frontiers for understanding fundamental neural system operations.

Glucagon-like peptide 1 receptor agonists (GLP1RAs) effectively reduce body weight and improve metabolic outcomes; however, established peptide-based therapies require injections and are complex to manufacture. Small-molecule GLP1RAs promise oral bioavailability and scalable manufacturing, but their selective binding to human versus rodent receptors has limited mechanistic studies. Here we developed humanized GLP1R mouse models to investigate how small-molecule GLP1RAs influence feeding behaviour. We found that these compounds regulate both homeostatic and hedonic feeding through parallel neural circuits. Beyond engaging canonical hypothalamic and hindbrain networks that control metabolic homeostasis, GLP1RAs recruit a discrete population of Glp1r-expressing neurons in the central amygdala, which selectively suppress the consumption of palatable foods by reducing dopamine release in the nucleus accumbens. Stimulating these central amygdalar neurons curtails hedonic feeding, whereas targeted deletion of the receptor in this cell population specifically diminishes the anorectic efficacy of GLP1RAs for reward-driven intake. These findings identify a neural circuit through which small-molecule GLP1RAs modulate reward processing, with implications for the treatment of substance-use disorder and binge eating.

The integration of synaptic inputs is a fundamental function of neurons. In the traditional model, excitatory inputs are summed at the soma to generate action potentials. However, how synaptic inputs are integrated by dendrites in vivo remains poorly explored. We used intravital two-photon dendritic imaging with a genetically encoded voltage indicator (accelerated sensor of action potentials 5) together with somatic whole-cell patch clamp recordings to investigate how synaptic depolarizations are transferred to the soma in pyramidal neurons of the mouse somatosensory cortex. We studied the integration of synaptic inputs under spontaneous and sensory-evoked conditions, as well as following electrical and optogenetic stimulation. In all cases, while multiple inputs evoked measurable depolarizations in the cell body, isolated synaptic potentials were strongly attenuated. Our results suggest that isolated synaptic inputs have a minimal contribution to somatic depolarization, whereas coincident inputs within short temporal windows are more effective, indicating a regime of dendritic integration that favors coincident or clustered neuronal activity in cortical networks.

Sub-millivolt membrane potential (V) dynamics in multicellular non-excitable networks have remained largely inaccessible due to insufficiently sensitive imaging tools. Here, we introduce rEstus2s, a next-generation genetically encoded voltage indicator that overcomes this barrier by enabling high-resolution V imaging. Using rEstus2s, we uncover bioelectric contact inhibition (BCI), a biophysical principle in which gap junction coupling passively stabilizes V by suppressing electrical volatility. We show that V variance scales inversely with network size (1/n), reflecting a transition from stochastic single-cell behavior to collective electrical stability. Ca²⁺-activated oncogenic ion channels, including ANO1 and K3.1, drive pronounced electrical volatility in isolated cells, but BCI effectively attenuates this volatility in electrically coupled networks. Disruption of gap junction coupling abolishes BCI and restores high electrical volatility. These findings establish a unifying framework for how multicellular systems maintain electrical homeostasis and reveal gap junction coupling as a key determinant of bioelectric stability in health and disease.

Striatal dopamine plays key roles in our normal and pathological goal-directed actions. To understand dopamine function, much attention has focused on how midbrain dopamine neurons modulate their firing patterns. However, we identify a presynaptic mechanism that triggers dopamine release directly, bypassing activity in dopamine neurons. We paired electrophysiological recordings of striatal channelrhodopsin2-expressing cholinergic interneurons with simultaneous detection of dopamine release at carbon-fiber microelectrodes in striatal slices. We reveal that activation of cholinergic interneurons by light flashes that cause only single action potentials in neurons from a small population triggers dopamine release via activation of nicotinic receptors on dopamine axons. This event overrides ascending activity from dopamine neurons and, furthermore, is reproduced by activating ChR2-expressing thalamostriatal inputs, which synchronize cholinergic interneurons in vivo. These findings indicate that synchronized activity in cholinergic interneurons directly generates striatal dopamine signals whose functions will extend beyond those encoded by dopamine neuron activity.

In this issue of Neuron, Threlfell et al. (2012) report that synchronous activation of cholinergic interneurons evokes striatal dopamine release by activating presynaptic nicotinic acetylcholine receptors. These findings call for a fundamental reevaluation of the long-standing view that dopamine and acetylcholine "feud" over control of striatal circuitry.

The present investigation had two aims: (1) to study responses of dopamine neurons to stimuli with attentional and motivational significance during several steps of learning a behavioral task, and (2) to study the activity of dopamine neurons during the performance of cognitive tasks known to be impaired after lesions of these neurons. Monkeys that had previously learned a simple reaction time task were trained to perform a spatial delayed response task via two intermediate tasks. During the learning of each new task, a total of 25% of 76 dopamine neurons showed phasic responses to the delivery of primary liquid reward, whereas only 9% of 163 neurons responded to this event once task performance was established. This produced an average population response during but not after learning of each task. Reward responses during learning were significantly more numerous and pronounced in area A10, as compared to areas A8 and A9. Dopamine neurons also showed phasic responses to the two conditioned stimuli. These were the instruction cue, which was the first stimulus in each trial and indicated the target of the upcoming arm movement (58% of 76 neurons during and 44% of 163 neurons after learning), and the trigger stimulus, which was a conditioned incentive stimulus predicting reward and eliciting a saccadic eye movement and an arm reaching movement (38% of neurons during and 40% after learning). None of the dopamine neurons showed sustained activity in the delay between the instruction and trigger stimuli that would resemble the activity of neurons in dopamine terminal areas, such as the striatum and frontal cortex. Thus, dopamine neurons respond phasically to alerting external stimuli with behavioral significance whose detection is crucial for learning and performing delayed response tasks. The lack of sustained activity suggests that dopamine neurons do not encode representational processes, such as working memory, expectation of external stimuli or reward, or preparation of movement. Rather, dopamine neurons are involved with transient changes of impulse activity in basic attentional and motivational processes underlying learning and cognitive behavior.

The cortex and basal ganglia exhibit interdependent changes during learning. However, it is not clear whether plasticity occurs sequentially or concurrently across these structures. To address this question, we simultaneously recorded cortical and striatal activity while training mice on a visuomotor association task that involved turning a wheel to move a stimulus from a cue position to a target position. Prior to the development of learned behavior, context-independent visual responses increased in the visual-recipient striatum. This was followed by the emergence of context-dependent stimulus responses in both the medial prefrontal cortex (mPFC) and the mPFC-recipient striatum at the onset of learned behavior. All of these regions also exhibited increased responses to stimuli in the rewarded target position. However, while the visual-recipient striatum was non-selective between cue and target stimuli, the mPFC and mPFC-recipient striatum switched from being target-stimulus responsive before learning to being cue-stimulus responsive after learning. Our results suggest that sensorimotor learning involves routing stimulus information first to the sensory striatum and then to frontal motor circuits.