BrainWAVE: A Flexible Method for Noninvasive Stimulation of Brain Rhythms across Species.

Rhythmic neural activity, which coordinates brain regions and neurons to achieve multiple brain functions, is impaired in many diseases. Despite the therapeutic potential of driving brain rhythms, methods to noninvasively target deep brain regions are limited. Accordingly, we recently introduced a noninvasive stimulation approach using flickering lights and sounds ("flicker"). Flicker drives rhythmic activity in deep and superficial brain regions. Gamma flicker spurs immune function, clears pathogens, and rescues memory performance in mice with amyloid pathology. Here, we present substantial improvements to this approach that is flexible, user-friendly, and generalizable across multiple experimental settings and species. We present novel open-source methods for flicker stimulation across rodents and humans. We demonstrate rapid, cross-species induction of rhythmic activity without behavioral confounds in multiple settings from electrophysiology to neuroimaging. This flicker approach provides an exceptional opportunity to discover the therapeutic effects of brain rhythms across scales and species.

Dopamine encodes real-time reward availability and transitions between reward availability states on different timescales.

Optimal behavior requires interpreting environmental cues that indicate when to perform actions. Dopamine is important for learning about reward-predicting events, but its role in adapting to inhibitory cues is unclear. Here we show that when mice can earn rewards in the absence but not presence of an auditory cue, dopamine level in the ventral striatum accurately reflects reward availability in real-time over a sustained period (80 s). In addition, unpredictable transitions between different states of reward availability are accompanied by rapid (~1-2 s) dopamine transients that deflect negatively at the onset and positively at the offset of the cue. This Dopamine encoding of reward availability and transitions between reward availability states is not dependent on reward or activity evoked dopamine release, appears before mice learn the task and is sensitive to motivational state. Our findings are consistent across different techniques including electrochemical recordings and fiber photometry with genetically encoded optical sensors for calcium and dopamine.

Learning from inhibition: Functional roles of hippocampal CA1 inhibition in spatial learning and memory.

Hippocampal inhibitory interneurons exert a powerful influence on learning and memory. Inhibitory interneurons are known to play a major role in many diseases that affect memory, and to strongly influence brain functions required for memory-related tasks. While previous studies involving genetic, optogenetic, and pharmacological manipulations have shown that hippocampal interneurons play essential roles in spatial and episodic learning and memory, exactly how interneurons affect local circuit computations during spatial navigation is not well understood. Given the significant anatomical, morphological, and functional heterogeneity in hippocampal interneurons, one may suspect cell-type specific roles in circuit computations. Here, we review emerging evidence of CA1 hippocampal interneurons' role in local circuit computations that support spatial learning and memory and discuss open questions about CA1 interneurons in spatial learning.

Alzheimer's pathology causes impaired inhibitory connections and reactivation of spatial codes during spatial navigation.

Synapse loss and altered synaptic strength are thought to underlie cognitive impairment in Alzheimer's disease (AD) by disrupting neural activity essential for memory. While synaptic dysfunction in AD has been well characterized in anesthetized animals and in vitro, it remains unknown how synaptic transmission is altered during behavior. By measuring synaptic efficacy as mice navigate in a virtual reality task, we find deficits in interneuron connection strength onto pyramidal cells in hippocampal CA1 in the 5XFAD mouse model of AD. These inhibitory synaptic deficits are most pronounced during sharp-wave ripples, network oscillations important for memory that require inhibition. Indeed, 5XFAD mice exhibit fewer and shorter sharp-wave ripples with impaired place cell reactivation. By showing inhibitory synaptic dysfunction in 5XFAD mice during spatial navigation behavior and suggesting a synaptic mechanism underlying deficits in network activity essential for memory, this work bridges the gap between synaptic and neural activity deficits in AD.

An Interaction between Serotonin Receptor Signaling and Dopamine Enhances Goal-Directed Vigor and Persistence in Mice.

The functionally selective 5-HT2C receptor ligand SB242084 can increase motivation and have rapid onset anti-depressant-like effects. We sought to identify the specific behavioral effects of SB242084 treatment and elucidate the mechanism in female and male mice. Using a quantitative behavioral approach, we determined that SB242084 increases the vigor and persistence of goal-directed activity across different types of physical work, particularly when work requirements are demanding. We found this influence of SB242084 on effort, rather than reward to be reflected in striatal DA measured during behavior. Using in vivo fast scan cyclic voltammetry, we found that SB242084 has no effect on reward-related phasic DA release in the NAc. Using in vivo microdialysis to measure tonic changes in extracellular DA, we also found no changes in the NAc. In contrast, SB242084 treatment increases extracellular DA in the dorsomedial striatum, an area that plays a key role in response vigor. These findings have several implications. At the behavioral level, this work shows that the capacity to work in demanding situations can be increased, without a generalized increase in motor activity or reward value. At the circuit level, we identified a pathway restricted potentiation of DA release and showed that this was the reason for the increased response vigor. At the cellular level, we show that a specific serotonin receptor cross talks to the DA system. Together, this information provides promise for the development of treatments for apathy, a serious clinical condition that can afflict patients with psychiatric and neurological disorders.SIGNIFICANCE STATEMENT Motivated behaviors are modulated by reward value, effort demands, and cost-benefit computations. This information drives the decision to act, which action to select, and the intensity with which the selected action is performed. Because these behavioral processes are all regulated by DA signaling, it is very difficult to influence selected aspects of motivated behavior without affecting others. Here we identify a pharmacological treatment that increases the vigor and persistence of responding in mice, without increasing generalized activity or changing reactions to rewards. We show that the 5-HT2C-selective ligand boosts motivation by potentiating activity-dependent DA release in the dorsomedial striatum. These results reveal a novel strategy for treating patients with motivational deficits, avolition, or apathy.