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The authors provide evidence that a cerebellum-like structure at the initial stage of mammalian auditory processing (the dorsal cochlear nucleus) functions to cancel out self-generated sounds. A similar function has been established for cerebellum-like structures in electroreceptive fish, suggesting a conserved function for these structures across vertebrates. The dorsal cochlear nucleus (DCN) integrates auditory nerve input with a diverse array of sensory and motor signals processed in circuitry similar to that of the cerebellum. Yet how the DCN contributes to early auditory processing has been a longstanding puzzle. Using electrophysiological recordings in mice during licking behavior, we show that DCN neurons are largely unaffected by self-generated sounds while remaining sensitive to external acoustic stimuli. Recordings in deafened mice, together with neural activity manipulations, indicate that self-generated sounds are cancelled by non-auditory signals conveyed by mossy fibers. In addition, DCN neurons exhibit gradual reductions in their responses to acoustic stimuli that are temporally correlated with licking. Together, these findings suggest that DCN may act as an adaptive filter for cancelling self-generated sounds. Adaptive filtering has been established previously for cerebellum-like sensory structures in fish, suggesting a conserved function for such structures across vertebrates.

The direct and indirect pathways of the basal ganglia have long been thought to mediate behavioral promotion and inhibition, respectively. However, this classic dichotomous model has been recently challenged. To better understand neural processes underlying reward-based learning and movement control, we recorded from direct (dSPNs) and indirect (iSPNs) pathway spiny projection neurons in the dorsomedial striatum of D1-Cre and D2-Cre mice performing a probabilistic Pavlovian conditioning task. dSPNs tend to increase activity while iSPNs decrease activity as a function of reward value, suggesting the striatum represents value in the relative activity levels of dSPNs versus iSPNs. Lick offset-related activity increase is largely dSPN selective, suggesting dSPN involvement in suppressing ongoing licking behavior. Rapid responses to negative outcome and previous reward-related responses are more frequent among iSPNs than dSPNs, suggesting stronger contributions of iSPNs to outcome-dependent behavioral adjustment. These findings provide new insights into striatal neural circuit operations. Classically the direct and indirect pathways of basal ganglia are understood to have opposing roles in movement and reward learning, but recent work suggests a more complicated view. Here the authors further study indirect and direct pathway neurons, in the context of a probabilistic reward task.

The Wistar Kyoto (WKY) rat has been proposed as a model of depression-like symptoms. However, anhedonia-a reduction in the response to normatively rewarding events-as a central depression symptom has yet to be fully assessed in this model. We compared WKY rats and Wistar controls, with stress-susceptibility examined by applying mild unpredictable stress to a subset of each group. Anhedonia-like behavior was assessed using microstructural analysis of licking behavior, where mean lick cluster size reflects hedonic responses. This was combined with tests of anticipatory contrast, where the consumption of a moderately palatable solution (4% sucrose) is suppressed in anticipation of a more palatable solution (32% sucrose). WKY rats displayed greatly attenuated hedonic reactions to sucrose overall, although their reactions retained some sensitivity to differences in sucrose concentration. They displayed normal reductions in consumption in anticipatory contrast, although the effect of contrast on hedonic reactions was greatly blunted. Mild stress produced overall reductions in sucrose consumption, but this was not exacerbated in WKY rats. Moreover, mild stress did not affect hedonic reactions or the effects of contrast. These results confirm that the WKY substrain expresses a direct behavioral analog of anhedonia, which may have utility for increasing mechanistic understanding of depression symptoms.

In the spinal cord, attenuation of the inhibitory action of glycine is related to an increase in both inflammatory and diabetic neuropathic pain; however, the glycine receptor involvement in diabetic neuropathy has not been reported. We determined the expression of the glycine receptor subunits (α1–α3 and β) in streptozotocin-induced diabetic Long–Evans rats by qPCR and Western blot. The total mRNA and protein expression (whole spinal cord homogenate) of the α1, α3, and β subunits did not change during diabetes; however, the α2 subunit mRNA, but not the protein, was overexpressed 45 days after diabetes induction. By contrast, the synaptic expression of the α1 and α2 subunits decreased in all the studied stages of diabetes, but that of the α3 subunit increased on day 45 after diabetes induction. Intradermal capsaicin produced higher paw-licking behavior in the streptozotocin-induced diabetic rats than in the control animals. In addition, the nocifensive response was higher at 45 days than at 20 days. During diabetes, the expression of the glycine receptor was altered in the spinal cord, which strongly suggests its involvement in diabetic neuropathy.

Classical conditioning is a fundamental associative learning process in which repeated pairings of a conditioned stimulus (CS) with an unconditioned stimulus (US) lead to the CS eliciting a conditioned response (CR). Previous research has identified key neural regions involved in processing reward-predicting cues and mediating licking behavior. However, the mechanisms that sustain high conditioned response rates across repeated sessions remain elusive, particularly regarding how the reward expectation is represented on a session-by-session basis. While early learning phases in classical conditioning have been extensively studied, the neural mechanisms that support consistent performance over time remain unclear. In this study, we sought to understand how cortical regions, particularly the posterior parietal cortex (PPC), contribute to maintaining high CR rates across sessions. Using the core complex framework derived from Integrated Information Theory (IIT), we explored the dynamics of neural networks during sessions of high CR performance. Our findings suggest that while traditional functional connectivity (FC) methods struggled to capture the complexity of sustained behavioral engagement, the core complex framework revealed key regions, notably the PPC, that were significantly correlated with enhanced CR sessions. This work suggests the potential role of the PPC in supporting reward expectations and maintaining consistent behavioral responses. By applying the core complex framework to investigate neural substrates of sustained behavior, we provide novel insights into the interaction of cortical networks during classical conditioning, offering promising directions for future research in associative learning and behavior.

An emerging literature suggests that the medial prefrontal cortex (mPFC) is crucial for the ability to track behavioral outcomes over time and has a critical role in successful foraging. Here, we examine this issue by analyzing changes in neuronal spike activity and local field potentials in the rat mPFC in relation to the consumption of rewarding stimuli. Using multi-electrode recording methods, we simultaneously recorded from ensembles of neurons and field potentials in the mPFC during the performance of an operant-delayed alternation task and a variable-interval licking procedure. In both tasks, we found that consummatory behavior (licking) activates many mPFC neurons and is associated with theta-band phase locking by mPFC field potentials. Many neurons that were modulated by the delivery of reward were also modulated when rats emitted bouts of licks during the period of consumption. The majority of these licking-modulated neurons were found in the rostral part of the prelimbic cortex, a region that is heavily interconnected with the gustatory insular cortex and projects to subcortical feeding-related centers. Based on the tight coupling between spike activity, theta-band phase locking, and licking behavior, we suggest that reward-related activity in the mPFC is driven by consummatory behavior.

Alzheimer’s disease (AD), a neurodegenerative disease, causes behavioural abnormalities such as disinhibition, impulsivity, and hyperphagia. Preclinical studies using AD model mice have investigated these phenotypes by measuring brain activity in awake, behaving mice. In this study, we monitored the behavioural alterations of impulsivity and hyperphagia in middle-aged AD model mice. As a behavioural readout, we trained the mice to accept a water-reward under thirsty conditions. To analyse brain activity, we developed a measure for licking behaviour combined with visualisation of whole brain activity using awake fMRI. In a water-reward learning task, the AD model mice showed significant hyperactivity of the dorsal raphe nucleus in thirsty conditions. In summary, we successfully visualised altered brain activity in AD model mice during reward-oriented behaviour for the first time using awake fMRI. This may help in understanding the causes of behavioural alterations in AD patients.

The discovery and development of new and potentially nonaddictive pain therapeutics requires rapid, yet clinically relevant assays of nociception in preclinical models. A reliable and scalable automated scoring system for nocifensive behavior of mice in the formalin assay would dramatically lower the time and labor costs associated with experiments and reduce experimental variability. Here, we present a method that exploits machine learning techniques for video recordings that consists of three components: key point detection, per frame feature extraction using these key points, and classification of behavior using the GentleBoost algorithm. This approach to automation is flexible as different model classifiers or key points can be used with only small losses in accuracy. The adopted system identified the behavior of licking/biting of the hind paw with an accuracy that was comparable to a human observer (98% agreement) over 111 different short videos (total 284 min) at a resolution of 1 s. To test the system over longer experimental conditions, the responses of two inbred strains, C57BL/6NJ and C57BL/6J, were recorded over 90 min post formalin challenge. The automated system easily scored over 80 h of video and revealed strain differences in both response timing and amplitude. This machine learning scoring system provides the required accuracy, consistency, and ease of use that could make the formalin assay a feasible choice for large-scale genetic studies.

We previously showed that mice that selectively and reversibly overexpress striatal D2 receptors (D2R-OE) model the negative symptoms of schizophrenia. Specifically, D2R-OE mice display a deficit in incentive motivation. The present studies investigated the basis for this deficit. First, we assessed whether hedonic reaction to reward is intact in D2R-OE mice. We assessed licking behavior and video-scored positive hedonic facial reactions to increasing concentrations of sucrose in control and D2R-OE mice. We found no difference between D2R-OE mice and controls in hedonic reactions. To further understand the basis of the motivational deficit, mice were given a choice between pressing a lever for access to a preferred reward (evaporated milk) or consuming a freely available less preferred reward (home-cage chow). D2R-OE mice pressed less for the preferred milk and consumed more of the freely available less preferred chow, indicating that striatal overexpression of postsynaptic D2Rs can alter cost/benefit computations, leading to a motivational deficit. This motivational impairment was ameliorated when the transgene was turned off and D2R levels were normalized. Such a deficit may arise from impaired ability to represent the value of future rewards. To test this, we used operant concurrent schedules and found reduced sensitivity to the value of future outcomes in D2R-OE mice. These results demonstrate for the first time in a transgenic animal model of schizophrenia a dissociation between hedonic reaction to reward and incentive motivation, and show a striking parallel to the proposed neurobiological and psychological mechanisms of impaired incentive motivation in schizophrenia.

The homeostatic need for sodium is one of the strongest motivational drives known in animals. Although the brain regions involved in the sensory detection of sodium levels have been mapped relatively well, data about the neural basis of the motivational properties of salt appetite, including a role for midbrain dopamine cells, have been inconclusive. Here, we employed a combination of fiber photometry, behavioral pharmacology and c-Fos immunohistochemistry to study the involvement of the mesocorticolimbic dopamine system in salt appetite in rats. We observed that sodium deficiency affected the responses of dopaminergic midbrain neurons to salt tasting, suggesting that these neurons encode appetitive properties of sodium. We further observed a significant reduction in the consumption of salt after pharmacological inactivation of the nucleus accumbens (but not the medial prefrontal cortex), and microstructure analysis of licking behavior suggested that this was due to decreased motivation for, but not appreciation of salt. However, this was not dependent on dopaminergic neurotransmission in that area, as infusion of a dopamine receptor antagonist into the nucleus accumbens did not alter salt appetite. We conclude that the nucleus accumbens, but not medial prefrontal cortex, is important for the behavioral expression of salt appetite by mediating its motivational component, but that the switch in salt appreciation after sodium depletion, although detected by midbrain dopamine neurons, must arise from other areas.