The thalamic reticular nucleus: a functional hub for thalamocortical network dysfunction in schizophrenia and a target for drug discovery

The thalamus (comprising many distinct nuclei) plays a key role in facilitating sensory discrimination and cognitive processes through connections with the cortex. Impaired thalamocortical processing has long been considered to be involved in schizophrenia. In this review we focus on the thalamic reticular nucleus (TRN) providing evidence for it being an important communication hub between the thalamus and cortex and how it may play a key role in the pathophysiology of schizophrenia. We first highlight the functional neuroanatomy, neurotransmitter localisation and physiology of the TRN. We then present evidence of the physiological roles of the TRN in relation to oscillatory activity, cognition and behaviour. Next we discuss the role of the TRN in rodent models of risk factors for schizophrenia (genetic and pharmacological) and provide evidence for TRN deficits in schizophrenia. Finally we discuss new drug targets for schizophrenia in relation to restoring TRN circuitry dysfunction

BDNF and JNK-signalling modulate cortical interneuron and perineuronal net development: implications for schizophrenia-linked 16p11.2 duplication syndrome

Schizophrenia is a neurodevelopmental disorder caused by the interaction of genetic and environmental risk factors. One of the strongest genetic risk variants is duplication of chr.16p11.2. Schizophrenia is characterised by cortical GABAergic interneuron dysfunction, and disruption to surrounding extracellular matrix structures, perineuronal nets (PNNs). Developmental maturation of GABAergic interneurons, and also the resulting closure of the critical period of cortical plasticity, is regulated by brain derived neurotrophic factor (BDNF), although the mechanisms involved are unknown. Here, we show that BDNF promotes GABAergic interneuron and PNN maturation through JNK signalling. In mice reproducing the 16p11.2 duplication, where the JNK upstream activator Taok2 is overexpressed, we find that JNK is overactive and there are developmental abnormalities in PNNs which persist into adulthood. Prefrontal cortex parvalbumin expression is reduced while PNN intensity is increased. Additionally, we report a unique role for TAOK2 signalling in the regulation of parvalbumin interneurons. Our work implicates TAOK2-JNK signalling in cortical interneuron and PNN development, and in the responses to BDNF. It also demonstrates that over-activation of this pathway in conditions associated with schizophrenia risk causes long-lasting disruption in cortical interneurons

Assessing the needs of older people in urban settings : integration of emotive, physiological and built environment data

Design of the built environment for navigability and walkability is an increasingly important aspect of urban planning. This focus derives in part from increasing interest in lifestyles and behaviours including level of physical activity and health outcomes. Geographical Information Systems and virtual realities are playing a significant role in advancing this agenda: examples exist of integrating qualitative data (words about or visual images of places) and quantitative data (numerical descriptions of places). However there remain opportunities for exploring alternative ways of linking different types of data (physiological measurements, emotional response, street walkability and urban design quality) to address issues of urban planning and renewal. Using a case study approach this paper explores the application of geographic information science and systems to participatory approaches in built environment planning with the aim of exploring older people’s response to an unfamiliar urban environment. It examines different ways of combining temporally and spatial referenced qualitative and quantitative data. The participants in the study were a group of 44 older people (60+) from Swansea, Wales, who viewed a filmed walking route around Colchester, England. Whilst viewing the film they gave an oral commentary and physiological readings were made, which have been integrated with primary data collected on the built environment along the walking route. Proximity and inverse distance weighting approaches for combining these datasets produce complementary results in respect of older people’s physiological and emotive response to variation in the walkability and design quality of a walking route through an unfamiliar town centre. The results reveal participants experienced an elevated average heart close to Colchester Town railway station and expressed a comparatively negative emotional response to this location. Conversely participants experienced lower average heart rate, indicating reduced stress, in Brook Street where the overall Urban Design Quality score was relatively low

The Ursinus Weekly, November 21, 1960

Miss Liberty Bowl title won by UC\u27s Sandra Motta • U. of P. chaplain speaks to Canterbury Club • Quiet hours enforced by W.S.G.A. senate • New Outing Club formed; Woodruff acting chairman • ICG makes plans to attend state convention in April • Dr. Baker and Dr. Zucker discuss disarmament at IRC meeting • Philadelphia orchestra presents second student concert, Dec. 6 • Phoenixville site of Phila. Civic Concert • Seminar accepts applications now • Young Republicans selected by NYR • Annual Messiah to be presented on Dec. 8th • Dark Victory to be presented by Curtain Club on December 9, 10 • Lutheran Club invites students to its first meeting tonight • Eight junior men nominated for Ruby business manager • Spanish Club sponsors Latin American parley • Lecture on French art heard by French Club • Editorial: Togetherness • Land of the midnight sun • For student teachers only • Other side of the desk • Outside reading • An incohesive account of things I saw in one weekend in New York • Head coach Fry is interviewed • Football statistics • St. Joe\u27s takes MASCAC honors • Curtis II intramural football champions • Soccer records winless season • Book review: Advise & consent • Sketches of Spain • Junior class Bowery held on November 19 • Ursinus Circle hears Dr. G.S. Pancoast speak • Ursinus coed exchange student now in Spain • Omega Chi sisters welcome ten pledges at pizza party • Poetry, short stories concern English Club at Dec. 9 meeting • Women\u27s Athletic Association sponsors bowling outinghttps://digitalcommons.ursinus.edu/weekly/1327/thumbnail.jp

Temporal dissociation of phencyclidine: Induced locomotor and social alterations in rats using an automated homecage monitoring system – implications for the 3Rs and preclinical drug discovery

Background: Rodent behavioural assays are widely used to delineate the mechanisms of psychiatric disorders and predict the efficacy of drug candidates. Conventional behavioural paradigms are restricted to short time windows and involve transferring animals from the homecage to unfamiliar apparatus which induces stress. Additionally, factors including environmental perturbations, handling and the presence of an experimenter can impact behaviour and confound data interpretation. To improve welfare and reproducibility these issues must be resolved. Automated homecage monitoring offers a more ethologically relevant approach with reduced experimenter bias. Aim: To evaluate the effectiveness of an automated homecage system at detecting locomotor and social alterations induced by phencyclidine (PCP) in group-housed rats. PCP is an NMDA receptor antagonist commonly utilised to model aspects of schizophrenia. Methods: Rats housed in groups of 3 were implanted with radio frequency identification (RFID) tags. Each homecage was placed over a RFID reader baseplate for the automated monitoring of the social and locomotor activity of each individual rat. For all rats, we acquired homecage data for 24 h following administration of both saline and PCP (2.5 mg/kg). Results: PCP resulted in significantly increased distance travelled from 15 to 60 min post injection. Furthermore, PCP significantly enhanced time spent isolated from cage-mates and this asociality lasted from 60 to 105 min post treatment. Conclusions: Unlike conventional assays, in-cage monitoring captures the temporal duration of drug effects on multiple behaviours in the same group of animals. This approach could benefit psychiatric preclinical drug discovery though improved welfare and increased between-laboratory replicability

Distortion of protein analysis in primary neuronal cultures by serum albumin from culture medium : a methodological approach to improve target protein quantification

BACKGROUND: Primary neuronal cultures underpin diverse neuroscience experiments, including various protein analysis techniques, such as Western blotting, whereby protein extraction from cultured neurons is required. During immunoblotting experiments, we encountered problems due to a highly-abundant protein of 65-70 KDa present in the cell extracts, that interfered with total protein estimation, and immunodetection of target proteins of similar size. Previous research has suggested that serum proteins, specifically albumin, contained within commonly-used culture media, can bind to, or be adsorbed by, generic cell culture plasticware. This residual albumin may then be extracted along with cell proteins. NEW METHOD: We made simple modifications to wash steps of traditional cell lysis/extraction protocols. RESULTS: We report that a substantial amount of albumin, accumulated from the standard culture media, is extracted from primary neuronal cultures along with the cellular contents. This contamination can be reduced, without changing the culture conditions, by modifying wash procedures. COMPARISON WITH EXISTING METHODS: Accumulated albumin from neuronal culture media, in amounts equivalent to cellular contents, can distort data from total protein assays and from the immunoreactive signal from nearby bands on Western blots. By altering wash protocols during protein extraction, these problems can be ameliorated. CONCLUSIONS: We suggest that the standard extended culture periods for primary neuronal cultures, coupled with the requirement for successive medium changes, may leave them particularly susceptible to cumulative albumin contamination from the culture media used. Finally, we propose the implementation of simple alterations to wash steps in protein extraction protocols which can ameliorate this interference

Enzymatic degradation of cortical perineuronal nets reverses GABAergic interneuron maturation

Perineuronal nets (PNNs) are specialised extracellular matrix structures which preferentially enwrap fast-spiking (FS) parvalbumin interneurons and have diverse roles in the cortex. PNN maturation coincides with closure of the critical period of cortical plasticity. We have previously demonstrated that BDNF accelerates interneuron development in a c-Jun-NH -terminal kinase (JNK)-dependent manner, which may involve upstream thousand-and-one amino acid kinase 2 (TAOK2). Chondroitinase-ABC (ChABC) enzymatic digestion of PNNs reportedly reactivates 'juvenile-like' plasticity in the adult CNS. However, the mechanisms involved are unclear. We show that ChABC produces an immature molecular phenotype in cultured cortical neurons, corresponding to the phenotype prior to critical period closure. ChABC produced different patterns of PNN-related, GABAergic and immediate early (IE) gene expression than well-characterised modulators of mature plasticity and network activity (GABA -R antagonist, bicuculline, and sodium-channel blocker, tetrodotoxin (TTX)). ChABC downregulated JNK activity, while this was upregulated by bicuculline. Bicuculline, but not ChABC, upregulated Bdnf expression and ERK activity. Furthermore, we found that BDNF upregulation of semaphorin-3A and IE genes was TAOK mediated. Our data suggest that ChABC heightens structural flexibility and network disinhibition, potentially contributing to 'juvenile-like' plasticity. The molecular phenotype appears to be distinct from heightened mature synaptic plasticity and could relate to JNK signalling. Finally, we highlight that BDNF regulation of plasticity and PNNs involves TAOK signalling. [Abstract copyright: © 2022. The Author(s).

The schizophrenia risk gene Map2k7 regulates responding in a novel contingency-shifting rodent touchscreen gambling task

ABSTRACT In schizophrenia, subjects show reduced ability to evaluate and update risk/reward contingencies, showing correspondingly suboptimal performance in the Iowa gambling task. JNK signalling gene variants are associated with schizophrenia risk, and JNK modulates aspects of cognition. We therefore studied the performance of mice hemizygous for genetic deletion of the JNK activator MKK7 (Map2k7+/− mice) in a touchscreen version of the Iowa gambling task, additionally incorporating a novel contingency-switching stage. Map2k7+/− mice performed slightly better than wild-type (WT) littermates in acquisition and performance of the task. Although Map2k7+/− mice adapted well to subtle changes in risk/reward contingencies, they were profoundly impaired when the positions of 'best' and 'worst' choice selections were switched, and still avoided the previous 'worst' choice location weeks after the switch. This demonstrates a precise role for MKK7–JNK signalling in flexibility of risk/reward assessment and suggests that genetic variants affecting this molecular pathway may underlie impairment in this cognitive domain in schizophrenia. Importantly, this new contingency shift adaptation of the rodent touchscreen gambling task has translational utility for characterising these cognitive subprocesses in models of neuropsychiatric disorders

Exploring metabolic pathway disruption in the subchronic phencyclidine model of schizophrenia with the generalized singular value decomposition

The quantification of experimentally-induced alterations in biological pathways remains a major challenge in systems biology. One example of this is the quantitative characterization of alterations in defined, established metabolic pathways from complex metabolomic data. At present, the disruption of a given metabolic pathway is inferred from metabolomic data by observing an alteration in the level of one or more individual metabolites present within that pathway. Not only is this approach open to subjectivity, as metabolites participate in multiple pathways, but it also ignores useful information available through the pairwise correlations between metabolites. This extra information may be incorporated using a higher-level approach that looks for alterations between a pair of correlation networks. In this way experimentally-induced alterations in metabolic pathways can be quantitatively defined by characterizing group differences in metabolite clustering. Taking this approach increases the objectivity of interpreting alterations in metabolic pathways from metabolomic data. We present and justify a new technique for comparing pairs of networks - in our case these networks are based on the same set of nodes and there are two distinct types of weighted edges. The algorithm is based on the Generalized Singular Value Decomposition (GSVD), which may be regarded as an extension of Principle Components Analysis to the case of two data sets. We show how the GSVD can be interpreted as a technique for reordering the two networks in order to reveal clusters that are exclusive to only one. Here we apply this algorithm to a new set of metabolomic data from the prefrontal cortex (PFC) of a translational model relevant to schizophrenia, rats treated subchronically with the N-methyl-D-Aspartic acid (NMDA) receptor antagonist phencyclidine (PCP). This provides us with a means to quantify which predefined metabolic pathways (Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolite pathway database) were altered in the PFC of PCP-treated rats. Several significant changes were discovered, notably: 1) neuroactive ligands active at glutamate and GABA receptors are disrupted in the PFC of PCP-treated animals, 2) glutamate dysfunction in these animals was not limited to compromised glutamatergic neurotransmission but also involves the disruption of metabolic pathways linked to glutamate; and 3) a specific series of purine reactions Xanthine Inosine adenylosuccinate is also disrupted in the PFC of PCP-treated animals. Network reordering via the GSVD provides a means to discover statistically validated differences in clustering between a pair of networks. In practice this analytical approach, when applied to metabolomic data, allows us to quantify the alterations in metabolic pathways between two experimental groups. With this new computational technique we identified metabolic pathway alterations that are consistent with known results. Furthermore, we discovered disruption in a novel series of purine reactions that may contribute to the PFC dysfunction and cognitive deficits seen in schizophrenia

Disruption of the Zdhhc9 intellectual disability gene leads to behavioural abnormalities in a mouse

Protein S-acylation is a widespread post-translational modification that regulates the trafficking and function of a diverse array of proteins. This modification is catalysed by a family of twenty-three zDHHC enzymes that exhibit both specific and overlapping substrate interactions. Mutations in the gene encoding zDHHC9 cause mild-to-moderate intellectual disability, seizures, speech and language impairment, hypoplasia of the corpus callosum and reduced volume of sub-cortical structures. In this study, we have undertaken behavioural phenotyping, magnetic resonance imaging (MRI) and isolation of S-acylated proteins to investigate the effect of disruption of the Zdhhc9 gene in mice in a C57BL/6 genetic background. Zdhhc9 mutant male mice exhibit a range of abnormalities compared with their wild-type littermates: altered behaviour in the open-field test, elevated plus maze and acoustic startle test that is consistent with a reduced anxiety level; a reduced hang time in the hanging wire test that suggests underlying hypotonia but which may also be linked to reduced anxiety; deficits in the Morris water maze test of hippocampal-dependent spatial learning and memory; and a 36% reduction in corpus callosum volume revealed by MRI. Surprisingly, membrane association and S-acylation of H-Ras was not disrupted in either whole brain or hippocampus of Zdhhc9 mutant mice, suggesting that other substrates of this enzyme are linked to the observed changes. Overall, this study highlights a key role for zDHHC9 in brain development and behaviour, and supports the utility of the Zdhhc9 mutant mouse line to investigate molecular and cellular changes linked to intellectual disability and other deficits in the human population