Group I mGluRs have diverse functions in some fundamental neuronal processes, including modulation of synaptic plasticity; and dysregulation of these receptors could lead to various neuropsychiatric disorders. Trafficking of Group I mGluRs plays critical roles in controlling the precise spatiotemporal localization and activity of these receptors, both of which contribute to proper downstream signaling. Using “molecular replacement” approach in hippocampal neurons derived from mice of both sexes, we demonstrate a critical role for the postsynaptic density protein Norbin in regulating the ligand-induced internalization of Group I mGluRs. We show that Norbin associates with protein kinase A (PKA) through its N-terminus and anchors mGluR5 through its C-terminus, both of which are necessary for the ligand-mediated endocytosis of mGluR5, a member of the Group I mGluR family. A point mutation (A687G) at the C-terminus of Norbin inhibits the binding of Norbin to mGluR5 and blocks mGluR5 endocytosis. Finally, we de...

The capacity to suppress learned responses is essential for animals to adapt in dynamic environments. Extinction is a process by which animals learn to suppress conditioned responding when an expected outcome is omitted. The infralimbic (IL) cortex to nucleus accumbens shell (NAcS) neural circuit is implicated in suppressing conditioned responding after extinction, especially in the context of operant cocaine-seeking behavior. However, the role of the IL-to-NAcS neural circuit in the extinction of responding to appetitive Pavlovian cues is unknown, and the psychological mechanisms involved in response suppression following extinction are unclear. We trained male Long Evans rats to associate a 10 s auditory conditioned stimulus (CS; 14 trials per session) with a sucrose unconditioned stimulus (US; 0.2 ml per CS) in a specific context, and then following extinction in a different context, precipitated a renewal of CS responding by presenting the CS alone in the original Pavlovian conditioning context. Unilat...

Taste buds contain multiple cell types, two of which mediate transduction of specific taste qualities: Type III cells transduce sour while Type II cells transduce either sweet, or bitter or umami. In order to discern the degree of interaction between different cell types and specificity of connectivity with the afferent nerve fibers (NFs), we employed serial blockface scanning electron microscopy (sbfSEM) through five circumvallate mouse taste buds. Points of contact between Type II and Type III cells are rare and lack morphologically identifiable synapses, suggesting that interaction between these cell types does not occur via synapses. Of the 127 NFs that make synaptic contacts with taste cells in the sampling volume, ∼70% ( n = 91) synapse with only one taste cell while 32 fibers synapse exclusively with multiple Type II cells or multiple Type III cells. Our data do not rule out multimodal fibers innervating Type II cells of separate taste qualities. Notably, four fibers (∼3%) synapse with both Type II ...

Running direction in the hippocampus is encoded by rate modulations of place field activity but also by spike timing correlations known as theta sequences. Whether directional rate codes and the directionality of place field correlations are related, however, has so far not been explored and therefore the nature of how directional information is encoded in the cornu ammonis remains unresolved. Here, using a previously published dataset that contains the spike activity of rat hippocampal place cells in the CA1, CA2 and CA3 subregions during free foraging of male Long-Evans rats in a 2D environment, we found that rate and spike timing codes are related. Opposite to a place field’s preferred firing rate direction spikes are more likely to undergo theta phase precession and, hence, more strongly impact paired correlations. Furthermore, we identified a subset of field pairs whose theta correlations are intrinsic in that they maintain the same firing order when the running direction is reversed. Both effects are...

The chemogenetic technology referred to as designer receptors exclusively activated by designer drugs (DREADDs) offers reversible means to control neuronal activity for investigating its functional correlation with behavioral action. Deschloroclozapine (DCZ), a recently-developed highly potent and selective DREADDs actuator, displays a capacity to expand the utility of DREADDs for chronic manipulation without side-effects in nonhuman primates, which has not yet been validated. Here we investigated the pharmacokinetics and behavioral effects of orally administered DCZ in female and male macaque monkeys. Pharmacokinetic analysis and positron emission tomography (PET) occupancy examination demonstrated that oral administration of DCZ yielded slower and prolonged kinetics, and that its bioavailability was 10-20% of that in the case of systemic injection. Oral DCZ (300-1000 μg/kg) induced significant working memory impairments for at least 4 h in monkeys with hM4Di expressed in the dorsolateral prefrontal corte...

The retrieval of recent and remote memories are thought to rely on distinct brain circuits and mechanisms. The retrosplenial cortex (RSC) is robustly activated during the retrieval of remotely acquired contextual fear memories (CFMs), but the contribution of particular subdivisions [granular (RSG) vs agranular retrosplenial area (RSA)] and the circuit mechanisms through which they interact to retrieve remote memories remain unexplored. In this study, using both anterograde and retrograde viral tracing approaches, we identified excitatory projections from layer 5 pyramidal neurons of the RSG to the CA1 stratum radiatum/lacunosum-moleculare of the dorsal hippocampus and the superficial layers of the RSA in male mice. We found that chemogenetic or optogenetic inhibition of the RSG-to-CA1, but not the RSG-to-RSA, pathway selectively impairs the retrieval of remote CFMs. Collectively, our results uncover a specific role for the RSG in remote CFM recall and provide circuit evidence that RSG-mediated remote CFM r...

In the article, “LRRK2 Inhibition Attenuates Microglial Inflammatory Responses,” by Mark S. Moehle, Philip J. Webber, Tonia Tse, Nour Sukar, David G. Standaert, Tara M. DeSilva, Rita M. Cowell, and Andrew B. West, which appeared on pages [1602–1611][1] of the February 1, 2012 issue, the

Auditory stimuli are often rhythmic in nature. Brain activity synchronizes with auditory rhythms via neural entrainment, and entrainment seems to be beneficial for auditory perception. However, it is not clear to what extent neural entrainment in the auditory system is reliable over time, which is a necessary prerequisite for targeted intervention. The current study aimed to establish the reliability of neural entrainment over time and to predict individual differences in auditory perception from associated neural activity. Across two different sessions, human listeners (21 females, 17 males) detected silent gaps presented at different phase locations of a 2 Hz frequency-modulated (FM) noise while EEG activity was recorded. As expected, neural activity was entrained by the 2 Hz FM noise. Moreover, gap detection was sinusoidally modulated by the phase of the 2 Hz FM into which the gap fell. Critically, both the strength of neural entrainment as well as the modulation of performance by the stimulus rhythm we...

Appropriate responding to threat and reward is essential to survival. The nucleus accumbens core (NAcc) is known to support and organize reward behavior. The NAcc is also necessary to fully discriminate threat and safety cues. To directly reveal NAcc threat firing, we recorded single-unit activity from seven female rats undergoing pavlovian fear discrimination. Rats fully discriminated danger, uncertainty, and safety cues, and most NAcc neurons showed the greatest firing change to danger and uncertainty. Heterogeneity in cue and reward firing led us to identify distinct functional populations. One NAcc population signaled threat, specifically decreasing firing to danger and uncertainty cues. A separate population signaled Bidirectional Valence, decreasing firing to the danger cue (negative valence), but increasing firing to reward (positive valence). The results reveal the NAcc to be a source of threat information and a more general valence hub. SIGNIFICANCE STATEMENT The nucleus accumbens core (NAcc) is ...