Stimuli that evoke the same feelings can nevertheless look different and have different semantic meanings. Although we know much about the neural representation of emotion, the neural underpinnings of emotional similarity are unknown. One possibility is that the same brain regions represent similarity between emotional and neutral stimuli, perhaps with different strengths. Alternatively, emotional similarity could be coded in separate regions, possibly those sensitive to emotional valence and arousal. In behaviour, the extent to which people consider similarity along emotional dimensions when they evaluate the overall similarity between stimuli has never been investigated. While the emotional features of stimuli may dominate explicit ratings of similarity, it is also possible that people neglect emotional dimensions as irrelevant to that judgement. We contrasted these hypotheses in (male and female) healthy controls using two measures of similarity and two picture databases of complex negative and neutral ...

Palmitoylation may be relevant to the processes of learning and memory, and even disorders such as post-traumatic stress disorder and aging-related cognitive decline. However, underlying mechanisms of palmitoylation in these processes remain unclear. Herein, we employed acyl-biotin exchange, co-immunoprecipitation and biotinylation assays, and behavioral and electrophysiological methods, to explore whether palmitoylation is required for hippocampal synaptic transmission and fear memory formation, and involved in functional modification of synaptic proteins such as PSD-95 and glutamate receptors, and detected if de-palmitoylation by specific enzymes has influence on glutamatergic synaptic plasticity. Our results showed that global palmitoylation level, palmitoylation of PSD-95 and glutamate receptors, post-synapse density-localization of PSD-95, surface expression of AMPARs, and synaptic strength of cultured hippocampal neurons, were all enhanced by TTX pretreatment, and these can be reversed by inhibition ...

Disorders of the medial temporal lobe (MTL) adversely affect visual working memory (vWM) performance, including feature binding. It is unclear whether these impairments generalise across visual dimensions or are specifically spatial. To address this issue, we compared performance in two tasks of thirteen epilepsy patients, who had undergone a temporal lobectomy, and fifteen healthy controls. In the vWM task, participants recalled the color of one of two polygons, previously displayed side by side. At recall, a location or shape probe identified the target. In the perceptual task, participants estimated the centroid of three visible disks. Patients recalled the target color less accurately than healthy controls because they frequently swapped the non-target with the target color. Moreover, healthy controls and right temporal lobectomy patients made more swap errors following shape than space probes. Left temporal lobectomy patients, showed the opposite pattern of errors instead. Patients and controls perfor...

Loneliness is a public health concern with detrimental effects on physical and mental well-being. Given phenotypical overlaps between loneliness and social anxiety (SA), cognitive-behavioral interventions targeting SA might be adopted to reduce loneliness. However, whether SA and loneliness share the same underlying neurocognitive mechanisms is still an elusive question. The current study aimed at investigating to what extent known behavioral and neural correlates of social avoidance in SA are evident in loneliness. We used a pre-stratified approach involving 42 (21 females) participants with high loneliness (HL) and 40 (20 females) participants with low loneliness (LL) scores. During functional magnetic resonance imaging, participants completed a social gambling task to measure the subjective value of engaging in social situations and responses to social feedback. Uni- and multivariate analyses of behavioral and neural data replicated known task effects. However, although HL participants showed increased ...

Abnormal involuntary movements, or dyskinesias, are seen in many neurological diseases, including disorders where the brain appears grossly normal. This observation suggests that alterations in neural activity or connectivity may underlie dyskinesias. One influential model proposes that involuntary movements are driven by an imbalance in the activity of striatal direct and indirect pathway neurons (dMSNs and iMSNs, respectively). Indeed, in some animal models, there is evidence that dMSN hyperactivity contributes to dyskinesia. Given the many diseases associated with dyskinesia, it is unclear if these findings generalize to all forms. Here, we used male and female mice in a mouse model of paroxysmal nonkinesigenic dyskinesia (PNKD) to assess whether involuntary movements are related to aberrant activity in the striatal direct and indirect pathways. In this model, as in the human disorder PNKD, animals experience dyskinetic attacks in response to caffeine or alcohol. Using optically identified striatal sing...

Acetylcholine is an important modulator of striatal activity and it is vital to controlling striatal-dependent behaviors, including motor and cognitive functions. Despite this significance, the mechanisms determining how acetylcholine impacts striatal signaling are still not fully understood. In particular, little is known about the role of nicotinic acetylcholine receptors (nAChRs) expressed by striatal interneurons. In the present study, we used fluorescent in situ hybridization (FISH) to determine which neuronal types express the most prevalent beta2 nicotinic subunit in the mouse striatum. Our data support a common view that nAChR expression is mostly restricted to striatal interneurons. Surprisingly though, cholinergic interneurons (CINs) were identified as a population with the highest expression of beta2 nicotinic subunit. To investigate the functional significance of beta2-containing nAChRs in striatal interneurons, we deleted them by injecting the AAV-Cre vector into the striatum of beta2-flox/flo...

Calretinin (CR) is a major calcium binding protein widely expressed in the central nervous system. However, its synaptic function remains largely elusive. At the auditory synapse of the endbulb of Held, CR is selectively expressed in different subtypes. Combining electrophysiology with immunohistochemistry, we investigated the synaptic transmission at the endbulb of Held synapses with and without endogenous CR expression in mature CBA/CAJ mice of either sex. Two synapse subtypes showed similar basal synaptic transmission, except a larger quantal size in CR-expressing synapses. During high-rate stimulus trains, CR-expressing synapses showed improved synaptic efficacy with significantly less depression and lower asynchronous release, suggesting more efficient exocytosis than non-CR-expressing synapses. Conversely, CR-expressing synapses had smaller readily releasable pool size, which was countered by higher release probability and faster synaptic recovery to support sustained release during high-rate activit...

Parkinson’s disease (PD) results from a loss of dopaminergic neurons. What triggers the break-down of neuronal signaling, and how this might be compensated, is not understood. The age of onset, progression and symptoms vary between patients, and our understanding of the clinical variability remains incomplete. In this study, we investigate this, by characterizing the dopaminergic landscape in healthy and denervated striatum, using biophysical modelling. Based on currently proposed mechanisms, we model three distinct denervation patterns, and show how this affect the dopaminergic network. Depending on the denervation pattern, we show how local and global differences arise in the activity of striatal neurons. Finally, we use the mathematical formalism to suggest a cellular strategy for maintaining normal dopamine signaling following neuronal denervation. This strategy is characterized by dual enhancement of both the release and uptake capacity of dopamine in the remaining neurons. Overall, our results derive...

Gonadotropin-releasing hormone (GnRH)-secreting neurons control fertility. The release of GnRH peptide regulates the synthesis and release of both LH and FSH from the anterior pituitary. While it is known that dopamine regulates GnRH neurons, the specific dopamine receptor subtype(s) involved remain unclear. Previous studies in adult rodents have reported juxtaposition of fibers containing tyrosine hydroxylase (TH), a marker of catecholaminergic cells, onto GnRH neurons and that exogenous dopamine inhibits GnRH neurons postsynaptically through dopamine D1-like and/or D2-like receptors. Our microarray data from GnRH neurons revealed a high level of Drd4 transcripts [i.e., dopamine D4 receptor (D4R)]. Single-cell RT-PCR and immunocytochemistry confirmed GnRH cells express the Drd4 transcript and protein, respectively. Calcium imaging identified changes in GnRH neuronal activity during application of subtype-specific dopamine receptor agonists and antagonists when GABAergic and glutamatergic transmission was ...

Genetic mutations in nitrogen permease regulator-like 2 (NPRL2) are associated with a wide spectrum of familial focal epilepsies, autism, and sudden unexpected death of epileptics (SUDEP), but the mechanisms by which NPRL2 contributes to these effects are not well known. NPRL2 is a requisite subunit of the Gap Activity TOward Rags 1 (GATOR1) complex, which functions as a negative regulator of mammalian Target Of Rapamycin Complex 1 (mTORC1) kinase when intracellular amino acids are low. Here we show that loss of NPRL2 expression in mouse excitatory glutamatergic neurons causes seizures prior to death, consistent with SUDEP in humans with epilepsy. Additionally, the absence of NPRL2 expression increases mTORC1-dependent signal transduction and significantly alters amino acid homeostasis in the brain. Loss of NPRL2 reduces dendritic branching and increases the strength of electrically stimulated action potentials in neurons. The increased action potential strength is consistent with elevated expression of ep...