Striatal ensemble activity in an innate naturalistic behavior.

Self-grooming is an innate, naturalistic behavior found in a wide variety of organisms. The control of rodent grooming has been shown to be mediated by the dorsolateral striatum through lesion studies and in-vivo extracellular recordings. Yet, it is unclear how populations of neurons in the striatum encode grooming. We recorded single-unit extracellular activity from populations of neurons in freely moving mice and developed a semi-automated approach to detect self-grooming events from 117 hours of simultaneous multi-camera video recordings of mouse behavior. We first characterized the grooming transition-aligned response profiles of striatal projection neuron and fast spiking interneuron single units. We identified striatal ensembles whose units were more strongly correlated during grooming than during the entire session. These ensembles display varied grooming responses, including transient changes around grooming transitions or sustained changes in activity throughout the duration of grooming. Neural trajectories computed from the identified ensembles retain the grooming related dynamics present in trajectories computed from all units in the session. These results elaborate striatal function in rodent self-grooming and demonstrate that striatal grooming-related activity is organized within functional ensembles, improving our understanding of how the striatum guides action selection in a naturalistic behavior.

Ketamine Rapidly Enhances Glutamate-Evoked Dendritic Spinogenesis in Medial Prefrontal Cortex Through Dopaminergic Mechanisms.

BACKGROUND: Ketamine elicits rapid onset antidepressant effects in patients with clinical depression through mechanisms hypothesized to involve the genesis of neocortical dendritic spines and synapses. Yet, the observed changes in dendritic spine morphology usually emerge well after ketamine clearance, raising questions about the link between rapid behavioral effects of ketamine and plasticity. METHODS: Here, we used two-photon glutamate uncaging/imaging to focally induce spinogenesis in the medial prefrontal cortex, directly interrogating baseline and ketamine-associated plasticity of deep layer pyramidal neurons in C57BL/6 mice. We combined pharmacological, genetic, optogenetic, and chemogenetic manipulations to interrogate dopaminergic mechanisms underlying ketamine-induced rapid enhancement in evoked plasticity and associated behavioral changes. RESULTS: We found that ketamine rapidly enhances glutamate-evoked spinogenesis in the medial prefrontal cortex, with timing that matches the onset of its behavioral efficacy and precedes changes in dendritic spine density. Ketamine increases evoked cortical spinogenesis through dopamine Drd1 receptor (Drd1) activation that requires dopamine release, compensating blunted plasticity in a learned helplessness paradigm. The enhancement in evoked spinogenesis after Drd1 activation or ketamine treatment depends on postsynaptic protein kinase A activity. Furthermore, ketamine's behavioral effects are blocked by chemogenetic inhibition of dopamine release and mimicked by activating presynaptic dopaminergic terminals or postsynaptic Gαs-coupled cascades in the medial prefrontal cortex. CONCLUSIONS: Our findings highlight dopaminergic mediation of rapid enhancement in activity-dependent dendritic spinogenesis and behavioral effects induced by ketamine.

Attenuated dopamine signaling after aversive learning is restored by ketamine to rescue escape actions.

Escaping aversive stimuli is essential for complex organisms, but prolonged exposure to stress leads to maladaptive learning. Stress alters neuronal activity and neuromodulatory signaling in distributed networks, modifying behavior. Here, we describe changes in dopaminergic neuron activity and signaling following aversive learning in a learned helplessness paradigm in mice. A single dose of ketamine suffices to restore escape behavior after aversive learning. Dopaminergic neuron activity in the ventral tegmental area (VTA) systematically varies across learning, correlating with future sensitivity to ketamine treatment. Ketamine's effects are blocked by chemogenetic inhibition of dopamine signaling. Rather than directly altering the activity of dopaminergic neurons, ketamine appears to rescue dopamine dynamics through actions in the medial prefrontal cortex (mPFC). Chemogenetic activation of Drd1 receptor positive mPFC neurons mimics ketamine's effects on behavior. Together, our data link neuromodulatory dynamics in mPFC-VTA circuits, aversive learning, and the effects of ketamine.

Over 264 million people around the world suffer from depression, according to the World Health Organization (WHO). Depression can be debilitating, and while anti-depressant drugs are available, they do not always work. A small molecule drug mainly used for anesthesia called ketamine has recently been shown to ameliorate depressive symptoms within hours, much faster than most anti-depressants. However, the molecular mechanisms behind this effect are still largely unknown. Most anti-depressant drugs work by restoring the normal balance of dopamine and other chemical messengers in the brain. Dopamine is released by a specialized group of cells called dopaminergic neurons, and helps us make decisions by influencing a wide range of other cells in the brain. In a healthy brain, dopamine directs us to rewarding choices, while avoiding actions with negative outcomes. During depression, these dopamine signals are perturbed, resulting in reduced motivation and pleasure. But it remained unclear whether ketamine's anti-depressant activity also relied on dopamine. To investigate this, Wu et al. used a behavioral study called "learned helplessness" which simulates depression by putting mice in unavoidable stressful situations. Over time the mice learn that their actions do not change the outcome and eventually stop trying to escape from unpleasant situations, even if they are avoidable. The experiment showed that dopaminergic neurons in an area of the brain that is an important part of the "reward and aversion" system became less sensitive to unpleasant stimuli following learned helplessness. When the mice received ketamine, these neurons recovered after a few hours. Individual mice also responded differently to ketamine. The most 'resilient', stress-resistant mice, which had distinct patterns of dopamine signaling, also responded most strongly to the drug. Genetic and chemical manipulation of dopaminergic neurons confirmed that ketamine needed intact dopamine signals to work, and revealed that it acted indirectly on dopamine dynamics via another brain region called the medial prefrontal cortex. These results shed new light on how a promising new anti-depressant works. In the future, they may also explain why drugs like ketamine work better for some people than others, ultimately helping clinicians select the most effective treatment for individual patients.

Wireless multilateral devices for optogenetic studies of individual and social behaviors.

Advanced technologies for controlled delivery of light to targeted locations in biological tissues are essential to neuroscience research that applies optogenetics in animal models. Fully implantable, miniaturized devices with wireless control and power-harvesting strategies offer an appealing set of attributes in this context, particularly for studies that are incompatible with conventional fiber-optic approaches or battery-powered head stages. Limited programmable control and narrow options in illumination profiles constrain the use of existing devices. The results reported here overcome these drawbacks via two platforms, both with real-time user programmability over multiple independent light sources, in head-mounted and back-mounted designs. Engineering studies of the optoelectronic and thermal properties of these systems define their capabilities and key design considerations. Neuroscience applications demonstrate that induction of interbrain neuronal synchrony in the medial prefrontal cortex shapes social interaction within groups of mice, highlighting the power of real-time subject-specific programmability of the wireless optogenetic platforms introduced here.

Ionic liquids with thioether motifs as synthetic cationic lipids for gene delivery.

This study introduces a novel class of imidazolium- and ammonium-based ionic liquids possessing two C12 and C14 tails and thioether linkers designed for lipoplex-mediated DNA delivery. Imidazolium-based ionic liquids displayed efficient gene delivery properties with low toxicity. Thiol-yne click chemistry was employed for the facile and robust synthesis of these thioether-based cationic lipioids with enhanced lipophilicity and low fluidity.