To efficiently process information, the brain shifts between encoding and retrieval states, prioritizing bottom-up or top-down processing accordingly. Expectation violation before or during learning has been shown to trigger an adaptive encoding mechanism, resulting in better memory for unexpected events. Using fMRI, we explored (1) whether this encoding mechanism is also triggered during retrieval, and if so, (2) what the temporal dynamics of its mnemonic consequences are. Male and female participants studied object images, then, with new objects, they learned a contingency between a cue and a semantic category. Rule-abiding (expected) and violating (unexpected) targets and similar foils were used at test. We found interactions between previous and current similar events’ expectation, such that when an expected event followed a similar but unexpected event, its performance was boosted, underpinned by activation in the hippocampus, midbrain, and occipital cortex. In contrast, a sequence of two unexpected s...

It is a commonly accepted view that light stimulation of mammalian photoreceptors causes a graded change in membrane potential instead of developing a spike. The presynaptic Ca2+ channels serve as a crucial link for the coding of membrane potential variations into neurotransmitter release. Cav1.4 L-type Ca2+ channels are expressed in photoreceptor terminals but the complete pool of Ca2+ channels in cone photoreceptors appears to be more diverse. Here, we discovered using whole-cell patch-clamp recording from cone photoreceptor terminals in both sexes of mice, that their Ca2+ currents are composed of low (T-type Ca2+ channels) and high (L-type Ca2+ channels) voltage-activated components. Furthermore, Ca2+ channels exerted self-generated spike behavior in dark membrane potentials, and spikes were generated in response to light/dark transition. The application of fast and slow Ca2+ chelators revealed that T-type Ca2+ channels are located close to the release machinery. Furthermore, capacitance measurements in...

Midbrain dopamine neurons play central physiological roles in voluntary movement, reward learning, and motivated behavior. Inhibitory signaling at somatodendritic dopamine D2 receptor (D2R) synapses modulates excitability of dopamine neurons. The neuropeptide neurotensin is expressed by many inputs to the midbrain and induces LTD of D2R synaptic currents (LTDDA); however, the source of neurotensin that is responsible for LTDDA is not known. Here we show, in brain slices from male and female mice, that LTDDA is driven by neurotensin released by dopamine neurons themselves. Optogenetic stimulation of dopamine neurons was sufficient to induce LTDDA in the substantia nigra, but not the VTA, and was dependent on neurotensin receptor signaling, postsynaptic calcium, and vacuolar-type H+-ATPase activity in the postsynaptic cell. These findings reveal a novel form of signaling between dopamine neurons involving release of the peptide neurotensin, which may act as a feedforward mechanism to increase dopamine neuron...

The lateral preoptic (LPO) hypothalamus is a center for NREM and REM sleep induction and NREM sleep homeostasis. Although LPO is needed for NREM sleep, we found that calcium signals were, surprisingly, highest in REM sleep. Furthermore, and equally surprising, NMDA receptors in LPO were the main drivers of excitation. Deleting the NMDA receptor GluN1 subunit from LPO abolished calcium signals in all cells and produced insomnia. Mice of both sexes had highly fragmented NREM sleep-wake patterns and could not generate conventionally classified REM sleep. The sleep phenotype produced by deleting NMDA receptors depended on where in the hypothalamus the receptors were deleted. Deleting receptors from the anterior hypothalamic area (AHA) did not influence sleep-wake states. The sleep fragmentation originated from NMDA receptors on GABA neurons in LPO. Sleep fragmentation could be transiently overcome with sleeping medication (zolpidem) or sedatives (dexmedetomidine; Dex). By contrast, fragmentation persisted unde...

Effective planning involves knowing where different actions take us. However, natural environments are rich and complex, leading to an exponential increase in memory demand as a plan grows in depth. One potential solution is to filter out features of the environment irrelevant to the task at hand. This enables a shared model of transition dynamics to be used for planning over a range of different input features. Here, we asked human participants (13 male, 16 female) to perform a sequential decision-making task, designed so that knowledge should be integrated independently of the input features (visual cues) present in one case but not in another. Participants efficiently switched between using a low-dimensional (cue independent) and a high-dimensional (cue specific) representation of state transitions. fMRI data identified the medial temporal lobe as a locus for learning state transitions. Within this region, multivariate patterns of BOLD responses were less correlated between trials with differing input f...

Motor skills learning is classically associated with brain regions including cerebral and cerebellar cortices and basal ganglia nuclei. Less is known about the role of the hippocampus in the acquisition and storage of motor skills. Here, we show that mice receiving a long-term training in the accelerating rotarod display marked hippocampal transcriptional changes and reduced pyramidal neurons activity in the CA1 region when compared with naive mice. Then, we use mice in which neural ensembles are permanently labeled in an Egr1 activity-dependent fashion. Using these mice, we identify a subpopulation of Egr1 -expressing pyramidal neurons in CA1 activated in short-term (STT) and long-term (LTT) trained mice in the rotarod task. When Egr1 is downregulated in the CA1 or these neuronal ensembles are depleted, motor learning is improved whereas their chemogenetic stimulation impairs motor learning performance. Thus, Egr1 organizes specific CA1 neuronal ensembles during the accelerating rotarod task that limit mo...

The imbalanced conditions of pronociceptive ON-cells and antinociceptive OFF-cells in the rostral ventromedial medulla (RVM) alter nociceptive transmission and play an important role in the development of chronic pain. This study aimed to explore the neuroplastic mechanisms of the RVM ON-cells and OFF-cells in a male rat model of experimental occlusal interference (EOI)-induced nociceptive behavior reflecting orofacial hyperalgesia and in modified models involving EOI removal at early and later stages. We recorded the mechanical head withdrawal thresholds, orofacial operant behaviors, and the activity of identified RVM ON-cells and OFF-cells in these rats. EOI-induced orofacial hyperalgesia could be relieved by EOI removal around postoperative day 3; this effect could be inhibited by intra-RVM microinjection of the κ-opioid receptor agonist U-69593. EOI removal around postoperative day 8 did not relieve the orofacial hyperalgesia, which could, however, be reversed by intra-RVM microinjection of the NK-1 (n...

The mechanistic target of rapamycin (mTOR) signaling pathway plays a major role in key cellular processes including metabolism and differentiation; however, the role of mTOR in microglia and its importance in Alzheimer's disease (AD) have remained largely uncharacterized. We report that selective loss of Tsc1 , a negative regulator of mTOR, in microglia in mice of both sexes, caused mTOR activation and upregulation of Trem2 with enhanced β-Amyloid (Aβ) clearance, reduced spine loss, and improved cognitive function in the 5XFAD AD mouse model. Combined loss of Tsc1 and Trem2 in microglia led to reduced Aβ clearance and increased Aβ plaque burden revealing that Trem2 functions downstream of mTOR. Tsc1 mutant microglia showed increased phagocytosis with upregulation of CD68 and Lamp1 lysosomal proteins. In vitro studies using Tsc1 -deficient microglia revealed enhanced endocytosis of the lysosomal tracker indicator Green DND-26 suggesting increased lysosomal activity. Incubation of Tsc1 -deficient microglia w...

Autism spectrum disorder (ASD) is a developmental disorder that is characterized by difficulties with social interaction and interpersonal communication. It has been argued that abnormal attentional function to exogenous stimuli precedes and contributes to the core ASD symptoms. Notably, the locus ceruleus (LC) and its noradrenergic projections throughout the brain modulate attentional function, but the extent to which this locus ceruleus–norepinephrine (LC–NE) system influences attention in individuals with ASD, who frequently exhibit dysregulated alerting and attention orienting, is unknown. We examined dynamic attention control in girls and boys with ASD at rest using the pupil dilation response (PDR) as a noninvasive measure of LC–NE activity. When gender- and age-matched neurotypical participants were passively exposed to an auditory stream, their PDR decreased for recurrent stimuli but remained sensitive to surprising deviant stimuli. In contrast, children with ASD showed less habituation to recurren...