Primary cilia are cellular appendages critical for diverse types of Signaling. They are found on most cell types, including cells throughout the CNS. Cilia preferentially localize certain G-protein-coupled receptors (GPCRs) and are critical for mediating the signaling of these receptors. Several of these neuronal GPCRs have recognized roles in feeding behavior and energy homeostasis. Cell and model systems, such as Caenorhabditis elegans and Chlamydomonas , have implicated both dynamic GPCR cilia localization and cilia length and shape changes as key for signaling. It is unclear whether mammalian ciliary GPCRs use similar mechanisms in vivo and under what conditions these processes may occur. Here, we assess two neuronal cilia GPCRs, melanin-concentrating hormone receptor 1 (MCHR1) and neuropeptide-Y receptor 2 (NPY2R), as mammalian model ciliary receptors in the mouse brain. We test the hypothesis that dynamic localization to cilia occurs under physiological conditions associated with these GPCR functions...

Wallerian degeneration (WD) occurs in the early stages of numerous neurologic disorders, and clarifying WD pathology is crucial for the advancement of neurologic therapies. ATP is acknowledged as one of the key pathologic substances in WD. The ATP-related pathologic pathways that regulate WD have been defined. The elevation of ATP levels in axon contributes to delay WD and protects axons. However, ATP is necessary for the active processes to proceed WD, given that WD is stringently managed by auto-destruction programs. But little is known about the bioenergetics during WD. In this study, we made sciatic nerve transection models for GO-ATeam2 knock-in rats and mice. We presented the spatiotemporal ATP distribution in the injured axons with in vivo ATP imaging systems, and investigated the metabolic source of ATP in the distal nerve stump. A gradual decrease in ATP levels was observed before the progression of WD. In addition, the glycolytic system and monocarboxylate transporters (MCTs) were activated in Sc...

Persistent neuronal firing is often observed in working memory and temporal association tasks both in humans and animals, and is believed to retain necessary information in these tasks. We have reported that hippocampal CA1 pyramidal cells are able to support persistent firing through intrinsic mechanisms in the presence of cholinergic agonists. However, it still remains largely unknown how persistent firing is affected by the development of animals and aging. Using in vitro patch-clamp recordings from CA1 pyramidal cells in rat brain slices, we first show that the cellular excitability of these aged rats was significantly lower than that of the young rats, responding with fewer spikes to current injection. In addition, we found age-dependent modulations of input resistance, membrane capacitance, and spike width. However, persistent firing in aged (approximately two-year-old) rats was as strong as that in young animals, and the properties of persistent firing were very similar among different age groups. I...

How an odor is perceived is to a large extent dependent on the context in which that odor is (or has been) experienced. For example, experiencing an odor in mixture with taste during consumption can instill taste qualities in the percept of that odor (e.g., vanilla, an odor, has a gustatory quality: sweet). How associative features of odors are encoded in the brain remains unknown, but previous work suggests an important role for ongoing interactions between piriform cortex and extraolfactory systems. Here, we tested the hypothesis that piriform cortex dynamically encodes taste associations of odors. Rats were trained to associate one of two odors with saccharin; the other odor remained neutral. Before and after training, we tested preferences for the saccharin-associated odor versus the neutral odor, and recorded spiking responses from ensembles of neurons in posterior piriform cortex (pPC) to intraoral delivery of small drops of the same odor solutions. The results show that animals successfully learned ...

The highly-conserved stomatin domain has been identified in genes throughout all classes of life. In animals, different stomatin domain-encoding genes have been implicated in the function of the kidney, red blood cells, and specific neuron types, although the underlying mechanisms remain unresolved. In one well-studied example of stomatin domain gene function, the Caenorhabditis elegans gene mec-2 and its mouse homolog Stoml3 are required for the function of mechanosensory neurons, where they modulate the activity of mechanosensory ion channels on the plasma membrane. Here, we identify an additional shared function for mec-2 and Stoml3 in a very different sensory context, that of olfaction. In worms, we find that a subset of stomatin domain genes are expressed in olfactory neurons, but only mec-2 is strongly required for olfactory behavior. mec-2 acts cell-autonomously and multiple alternatively-spliced isoforms of mec-2 can be substituted for each other. We generate a Stoml3 knock-out (KO) mouse and demon...

There is substantial variation in the mean and variance of light levels (luminance and contrast) in natural visual scenes. Retinal ganglion cells maintain their sensitivity despite this variation using two adaptive mechanisms, which control how responses depend on luminance and on contrast. However, the nature of each mechanism and their interactions downstream of the retina are unknown. We recorded neurons in the magnocellular and parvocellular layers of the lateral geniculate nucleus (LGN) in anesthetized adult male macaques and characterized how their responses adapt to changes in contrast and luminance. As contrast increases, neurons in the magnocellular layers maintain sensitivity to high temporal frequency stimuli but attenuate sensitivity to low-temporal frequency stimuli. Neurons in the parvocellular layers do not adapt to changes in contrast. As luminance increases, both magnocellular and parvocellular cells increase their sensitivity to high-temporal frequency stimuli. Adaptation to luminance is ...

State-of-the-art all-optical systems promise unprecedented access to neural activity in vivo , using multiphoton optogenetics to allow simultaneous imaging and control of activity in selected neurons at cellular resolution. However, to achieve wide use of all-optical stimulation and imaging, simple strategies are needed to robustly and stably express opsins and indicators in the same cells. Here, we describe a bicistronic adeno-associated virus (AAV) that expresses both the fast and bright calcium indicator jGCaMP8s, and a soma-targeted (st) and two-photon-activatable opsin, ChrimsonR. With this method, stChrimsonR stimulation with two-photon holography in the visual cortex of mice drives robust spiking in targeted cells, and neural responses to visual sensory stimuli and spontaneous activity are strong and stable. Cells expressing this bicistronic construct show responses to both photostimulation and visual stimulation that are similar to responses measured from cells expressing the same opsin and indicat...

Autoimmune encephalitis (AIE) associated with antibodies directed against the leucine-rich glioma inactivated 1 (LGI1) protein is the second most common AIE and is responsible for deleterious neocortical and limbic epileptic seizures. Previous studies demonstrated a pathogenic role of anti-LGI1 antibodies via alterations in the expression and function of Kv1 channels and AMPA receptors. However, the causal link between antibodies and epileptic seizures has never been demonstrated. Here, we attempted to determine the role of human anti-LGI1 autoantibodies in the genesis of seizures by analyzing the impact of their intracerebral injection in rodents. Acute and chronic injections were performed in rats and mice in the hippocampus and primary motor cortex, the two main brain regions affected by the disease. Acute infusion of CSF or serum IgG of anti-LGI1 AIE patients did not lead to the emergence of epileptic activities, as assessed by multisite electrophysiological recordings over a 10 h period after injectio...

Rodent studies suggest that spike timing relative to hippocampal theta activity determines whether potentiation or depression of synapses arise. Such changes also depend on spike timing between presynaptic and postsynaptic neurons, known as spike timing-dependent plasticity (STDP). STDP, together with theta phase-dependent learning, has inspired several computational models of learning and memory. However, evidence to elucidate how these mechanisms directly link to human episodic memory is lacking. In a computational model, we modulate long-term potentiation (LTP) and long-term depression (LTD) of STDP, by opposing phases of a simulated theta rhythm. We fit parameters to a hippocampal cell culture study in which LTP and LTD were observed to occur in opposing phases of a theta rhythm. Further, we modulated two inputs by cosine waves with 0° and asynchronous phase offsets and replicate key findings in human episodic memory. Learning advantage was found for the in-phase condition, compared with the out-of-pha...

Relapse is a major problem in treating methamphetamine use disorder. “Incubation of craving” during abstinence is a rat model for persistence of vulnerability to craving and relapse. While methamphetamine incubation has previously been demonstrated in male and female rats, it has not been demonstrated after withdrawal periods greater than 51 d and most mechanistic work used males. Here, we address both gaps. First, although methamphetamine intake was higher in males during self-administration training (6 h/d × 10 d), incubation was similar in males and females, with “incubated” craving persisting through withdrawal day (WD)100. Second, using whole-cell patch-clamp recordings in medium spiny neurons (MSNs) of the nucleus accumbens (NAc) core, we assessed synaptic levels of calcium-permeable AMPA receptors (CP-AMPARs), as their elevation is required for expression of incubation in males. In both sexes, compared with saline-self-administering controls, CP-AMPAR levels were significantly higher in methamphetam...