Motor skill learning induces changes in synaptic structure and function in the primary motor cortex. In the Fragile X Syndrome (FXS) mouse model an impairment in motor skill learning and associated formation of new dendritic spines was previously reported. However, whether modulation of synaptic strength through trafficking of AMPA receptors with motor skill training is impaired in FXS is not known. Here we performed in vivo imaging of a tagged AMPA receptor subunit, GluA2, in layer (L) 2/3 neurons in the primary motor cortex of wild type and Fmr1 KO male mice at different stages of learning a single forelimb-reaching task. Surprisingly, in the Fmr1 KO mice, despite impairments in learning there was no deficit in motor skill training-induced spine formation. However, the gradual accumulation of GluA2 in WT stable spines, which persists after training is completed and past the phase of spine number normalization, is absent in the Fmr1 KO mouse. These results demonstrate that motor skill learning not only re...

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 extra-olfactory 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 intra-oral delivery of small drops of the same odor solutions. The results show that animals successfully learned t...

Wallerian Degeneration (WD) occurs in the early stages of numerous neurological disorders, and clarifying WD pathology is crucial for the advancement of neurological therapies. Adenosine triphosphate (ATP) is acknowledged as one of the key pathological substances in WD. The ATP-related pathological pathways that regulate WD have been defined. The elevation of ATP levels in axon contributes to delay WD and protects axons. While, ATP is necessary for the active processes to proceed WD, given that WD is stringently managed by auto-destruction programs. However, 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 tran...

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 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 (~2 years old) rats was as strong as that in young animals, and the properties of persistent firing were very similar among different age groups. In addition, spike afte...

Studies in cultured neurons have shown that neurofilaments are cargoes of axonal transport that move rapidly but intermittently along microtubule tracks. However, the extent to which axonal neurofilaments move in vivo has been controversial. Some researchers have proposed that most axonally transported neurofilaments are deposited into a persistently stationary network and that only a small proportion of axonal neurofilaments are transported in mature axons. Here we use the fluorescence photoactivation pulse-escape technique to test this hypothesis in intact peripheral nerves of adult male hThy1-paGFP-NFM mice, which express low levels of mouse neurofilament protein M tagged with photoactivatable GFP. Neurofilaments were photoactivated in short segments of large, myelinated axons and the mobility of these fluorescently tagged polymers was determined by analyzing the kinetics of their departure. Our results show that >80% of the fluorescence departed the window within 3 hours after activation, indicating a ...

Cell birth and survival in the adult hippocampus are regulated by a circadian clock. Rotating shift work and jet lag disrupt circadian rhythms and aggravate disease. Internal misalignment, a state in which abnormal phase relationships prevail between and within organs, is proposed to account for adverse effects of circadian disruption. This hypothesis has been difficult to test because phase shifts of the entraining cycle inevitably lead to transient desynchrony. Thus, it remains possible that phase shifts, regardless of internal desynchrony, account for adverse effects of circadian disruption and alter neurogenesis and cell fate. In order to address this question, we examined cell birth and differentiation in the duper Syrian hamster ( Mesocricetus auratus ), a Cry1 -null mutant in which re-entrainment of locomotor rhythms is greatly accelerated. Adult females were subjected to alternating 8h advances and delays at eight 16-day intervals. BrdU, a cell birth marker, was given midway through the experiment...

Studies of ongoing, rapid motor behaviours have often focused on the decision-making implicit in the task. Here, we instead study how decision-making integrates with the perceptual and motor systems and propose a framework of limited-capacity, pipelined processing with flexible resources to understand rapid motor behaviours. Results from three experiments show that human performance is consistent with our framework: participants perform objectively worse as task difficulty increases and, surprisingly, this drop in performance is largest for the most skilled performers. As well, our analysis shows that the worst-performing participants can perform equally well under increased task demands, which is consistent with flexible neural resources being allocated to reduce bottleneck effects and improve overall performance. We conclude that capacity limits lead to information bottlenecks and that processes like attention help reduce the effects that these bottlenecks have on maximal performance. Significance State...

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 ...

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, though the underlying mechanisms remain unresolved. In one well-studied example of stomatin domain gene function, the C. elegans gene mec-2 and its mouse homologue 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 knockout mouse and demonstrate that, like i...

Allopregnanolone (AlloP) is a neurosteroid that potentiates ionotropic GABAergic (GABAA) inhibition and is approved for treating postpartum depression in women. Although the antidepressant mechanism of AlloP is largely unknown, it could involve selective action at GABAA receptors containing the δ subunit. Despite previous evidence for selective effects of AlloP on α4/δ-containing receptors of hippocampal dentate granule cells (DGCs), other recent results failed to demonstrate selectivity at these receptors ([Lu et al., 2020][1]). In contrast to DGCs, hippocampal fast-spiking parvalbumin (PV) interneurons express an unusual variant partnership of δ subunits with α1 subunits. Here, we hypothesized that native α1/δ receptors in hippocampal fast-spiking interneurons may provide a preferred substrate for AlloP. Contrary to the hypothesis, electrophysiology from genetically tagged PV interneurons in hippocampal slices from male mice showed that 100 nm AlloP promoted phasic inhibition by increasing the sIPSC deca...