Learning-dependent increases in sleep spindle density have been reported during nocturnal sleep immediately after the learning session. Here, we investigated experience-dependent changes in daytime sleep EEG activity after declarative learning of unrelated word pairs. At weekly intervals, 13 young male volunteers spent three 24 h sessions in the laboratory under carefully controlled homeostatic and circadian conditions. At approximately midday, subjects performed either one of two word-pair learning tasks or a matched nonlearning control task, in a counterbalanced order. The two learning lists differed in the level of concreteness of the words used, resulting in an easier and a more difficult associative encoding condition, as confirmed by performance at immediate cued recall. Subjects were then allowed to sleep for 4 h; afterward, delayed cued recall was tested. Compared with the control condition, sleep EEG spectral activity in the low spindle frequency range and the density of low-frequency sleep spindl...

In primates, working memory function depends on activity in a distributed network of cortical areas that display different patterns of delay task-related activity. These differences are correlated with, and might depend on, distinctive properties of the neurons located in each area. For example, layer 3 pyramidal neurons (L3PNs) differ significantly between primary visual and dorsolateral prefrontal (DLPFC) cortices. However, to what extent L3PNs differ between DLPFC and other association cortical areas is less clear. Hence, we compared the properties of L3PNs in monkey DLPFC versus posterior parietal cortex (PPC), a key node in the cortical working memory network. Using patch-clamp recordings and biocytin cell filling in acute brain slices, we assessed the physiology and morphology of L3PNs from monkey DLPFC and PPC. The L3PN transcriptome was studied using laser microdissection combined with DNA microarray or quantitative PCR. We found that in both DLPFC and PPC, L3PNs were divided into regular spiking (...

Some people are more willing to make immediate, risky, or costly reward-focused choices than others, which has been hypothesized to be associated with individual differences in dopamine (DA) function. In two studies using PET imaging, one empirical (Study 1: N = 144 males and females across 3 samples) and one meta-analytic (Study 2: N = 307 across 12 samples), we sought to characterize associations between individual differences in DA and time, probability, and physical effort discounting in human adults. Study 1 demonstrated that individual differences in DA D2-like receptors were not associated with time or probability discounting of monetary rewards in healthy humans, and associations with physical effort discounting were inconsistent across adults of different ages. Meta-analytic results for temporal discounting corroborated our empirical finding for minimal effect of DA measures on discounting in healthy individuals but suggested that associations between individual differences in DA and reward discou...

The endocannabinoid system plays important roles in brain development, but mechanistic studies have focused on neuronal differentiation, migration, and synaptogenesis, with less attention to transcellular interactions that coordinate neurodevelopmental processes across developing neural networks. We determined that, in the developing rodent cerebellar cortex (of both sexes), there is a transient window when the dominant brain cannabinoid receptor, CB1R, is expressed on afferent terminals instead of output neuron Purkinje cell synapses that dominate the adult cerebellum. Activation of these afferent CB1Rs suppresses synaptic transmission onto developing granule cells, and consequently also suppresses excitation of downstream neurons in the developing cortical network, including nonsynaptic, migrating neurons. Application of a CB1R antagonist during afferent stimulation trains and depolarizing voltage steps caused a significant, sustained potentiation of synaptic amplitude. Our data demonstrate that transien...

Maladaptive decision-making is increasingly recognized to play a significant role in numerous psychiatric disorders, such that therapeutics capable of ameliorating core impairments in judgment may be beneficial in a range of patient populations. The field of “decision neuroscience” is therefore in its ascendancy, with researchers from diverse fields bringing their expertise to bear on this complex and fascinating problem. In addition to the advances in neuroimaging and computational neuroscience that contribute enormously to this area, an increase in the complexity and sophistication of behavioral paradigms designed for nonhuman laboratory animals has also had a significant impact on researchers' ability to test the causal nature of hypotheses pertaining to the neural circuitry underlying the choice process. Multiple such decision-making assays have been developed to investigate the neural and neurochemical bases of different types of cost/benefit decisions. However, what may seem like relatively trivial v...

The substantia nigra pars reticulata (SNr), where the basal ganglia (BG) direct and indirect pathways converge, contains among the highest expression of cannabinoid receptor type 1 (CB1r) in the brain. Hence, SNr is an ideal locus to study pathway interactions and cannabinergic modulations. The objective of this study was to characterize the effects of systemic injections of the CB1r agonist (CP55940) on the balanced activity of the direct/indirect pathways in the SNr and its associated behaviors. To this aim, we recorded somatosensory and pathway-specific representations in the spiking activity of the SNr of male rats under CP55940. CB1r activation mainly decreased the inhibitory, potentially direct pathway component while sparing the excitatory, potentially indirect pathway component of somatosensory responses. As a result, cutaneous stimulation produced unbalanced responses favoring increased SNr firing rates, suggesting a potential locus for cannabinergic motor-related effects. To test this hypothesis,...

Dynamic regulation of synaptic transmission at cortical inputs to the dorsal striatum is considered critical for flexible and efficient action learning and control. Presynaptic mechanisms governing the properties and plasticity of glutamate release from these inputs are not fully understood, and the corticostriatal synaptic processes that support normal action learning and control remain unclear. Here we show in male and female mice that conditional deletion of presynaptic proteins RIM1αβ (RIM1) from excitatory cortical neurons impairs corticostriatal synaptic transmission in the dorsolateral striatum. Key forms of presynaptic G-protein-coupled receptor-mediated short- and long-term striatal plasticity are spared following RIM1 deletion. Conditional RIM1 KO mice show heightened novelty-induced locomotion and impaired motor learning on the accelerating rotarod. They further show heightened self-paced instrumental responding for food and impaired learning of a habitual instrumental response strategy. Togethe...

Glucocorticoid negative feedback in the brain controls stress, feeding, and neural-immune interactions by regulating the hypothalamic—pituitary—adrenal axis, but the mechanisms of inhibition of hypothalamic neurosecretory cells have never been elucidated. Using whole-cell patch-clamp recordings in an acute hypothalamic slice preparation, we demonstrate a rapid suppression of excitatory glutamatergic synaptic inputs to parvocellular neurosecretory neurons of the hypothalamic paraventricular nucleus (PVN) by the glucocorticoids dexamethasone and corticosterone. The effect was maintained with dexamethasone conjugated to bovine serum albumin and was not seen with direct intracellular glucocorticoid perfusion via the patch pipette, suggesting actions at a membrane receptor. The presynaptic inhibition of glutamate release by glucocorticoids was blocked by postsynaptic inhibition of G-protein activity with intracellular GDP-β-S application, implicating a postsynaptic G-protein-coupled receptor and the release of ...

Alzheimer's disease and other tauopathies have recently been clustered with a group of nervous system disorders termed protein misfolding diseases. The common element established between these disorders is their requirement for processing by the chaperone complex. It is now clear that the individual components of the chaperone system, such as Hsp70 and Hsp90, exist in an intricate signaling network that exerts pleiotropic effects on a host of substrates. Therefore, we have endeavored to identify new compounds that can specifically regulate individual components of the chaperone family. Here, we hypothesized that chemical manipulation of Hsp70 ATPase activity, a target that has not previously been pursued, could illuminate a new pathway toward chaperone-based therapies. Using a newly developed high-throughput screening system, we identified inhibitors and activators of Hsp70 enzymatic activity. Inhibitors led to rapid proteasome-dependent tau degradation in a cell-based model. Conversely, Hsp70 activators p...

Alternative splicing of the P/Q-type channel (CaV2.1) promises customization of the computational repertoire of neurons. Here we report that concerted splicing of its main α1A subunit, at both an EF-hand-like domain and the channel C terminus, controls the form of Ca2+-dependent facilitation (CDF), an activity-dependent enhancement of channel opening that is triggered by calmodulin. In recombinant channels, such alternative splicing switches CDF among three modes: (1) completely “ON” and driven by local Ca2+ influx through individual channels, (2) completely “OFF,” and (3) partially OFF but inducible by elevated global Ca2+ influx. Conversion from modes 1 to 3 represents an unprecedented dimension of control. The physiological function of these variants is likely important, because we find that the distribution of EF-hand splice variants is strikingly heterogeneous in the human brain, varying both across regions and during development.