Biology subjects

Nithianantharajah, J.

Publications and source records attributed to Nithianantharajah, J..

6 recordsLinked to original sources

bioRxiv2022

Mouse behaviour on the trial-unique non-matching-to-location (TUNL) touchscreen task reflects a mixture of distinct working memory codes and response biases

The trial-unique non-matching to location (TUNL) touchscreen task shows promise as a translational assay of working memory deficits in disorders including autism, ADHD, and schizophrenia. Although it is commonly assumed that the TUNL task predominantly measures spatial working memory in rodents, this proposition has not previously been tested. In this project, we used computational modelling of behaviour from mice performing the TUNL task (total N = 163 mice across three datasets; 158,843 total trials). Contrary to common assumptions, behaviour on the TUNL task did not exclusively reflect spatial working memory. Instead, choice behaviour was explained as a mixture of both retrospective (spatial) working memory and prospective working memory for an intended behavioural response, as well as animal-specific response biases. We suggest that these findings can be understood within a resource-rational cognitive framework, and propose several task-design principles that we predict will maximise spatial working memory and minimise alternative behavioural strategies.

animal behavior and cognition↗

bioRxiv2022

Gpr88 deletion impacts motivational control independently of striatal dopamine function

BackgroundDisrupted motivational control is a common--but poorly treated--feature of psychiatric disorders. Aberrant mesolimbic dopamine signalling is implicated in motivational symptoms, however direct manipulations to these pathways have yielded suboptimal therapeutic effects. GPR88 is an orphan G protein-coupled receptor highly expressed in the striatum on medium spiny neurons, and therefore well-placed to modulate striatal signalling. While the phenotype of Gpr88 knockout mice supports a disruption of motivational pathways, it is unclear whether GPR88 is involved in reward valuation and/or effort-based decision making in a sex-dependent manner, and if this involves altered dopamine function. MethodsIn male and female Gpr88 knockout mice, we used touchscreen-based progressive ratio, with and without reward devaluation, and effort-related choice tasks to assess motivation and cost/benefit decision making, respectively. To explore whether these motivational behaviours were related to altered striatal dopamine, we quantified expression of dopamine-related genes and/or proteins, and used [18F]DOPA PET and GTP{gamma}[35S] binding to assess pre- and postsynaptic dopamine function, respectively. ResultsWe show that male and female Gpr88 knockout mice display greater motivational drive than wild-type mice, which was maintained following reward devaluation. Further, we show that cost/benefit decision making is impaired in male, but not female, Gpr88 knockout mice. Surprisingly, we found that Gpr88 deletion had no effect on striatal dopamine by any of the measures assessed. ConclusionOur results highlight that GPR88 regulates motivational control of behaviour through a dopaminergic-independent mechanism, providing further support for GPR88 as target for mood symptoms in psychiatric disorders.

neuroscience↗

bioRxiv2021

Postsynaptic neuroligin-1 mediates presynaptic endocytosis during neuronal activity

Fast, high-fidelity neurotransmission and synaptic efficacy requires tightly regulated coordination of pre- and postsynaptic compartments and alignment of presynaptic release sites with postsynaptic receptor nanodomains. Neuroligin-1 (Nlgn-1) is a postsynaptic cell-adhesion protein exclusively localised to excitatory synapses that is crucial for coordinating the transsynaptic alignment of presynaptic release sites with postsynaptic AMPA receptors as well as postsynaptic transmission and plasticity. However, little is understood about whether the postsynaptic machinery can mediate the molecular architecture and activity of the presynaptic nerve terminal, and thus it remains unclear whether there are presynaptic contributions to Nlgn1-dependent control of signalling and plasticity. Here, we employed a presynaptic reporter of neurotransmitter release and synaptic vesicle dynamics, synaptophysin-pHluorin (sypHy), to directly assess the presynaptic impact of loss of Nlgn1. We show that lack of Nlgn1 had no effect on the size of the readily releasable or entire recycling pool of synaptic vesicles, nor did it impact exocytosis. However, we observed significant changes in the retrieval of synaptic vesicles by compensatory endocytosis, specifically during activity. Our data extends growing evidence that synaptic adhesion molecules critical for forming transsynaptic scaffolds are also important for regulating activity-induced endocytosis at the presynapse.

neuroscience↗

bioRxiv2020

Associative Learning and Motivation Differentially Requires Neuroligin-1 at Excitatory Synapses

In a changing environment, a challenge for the brain is to flexibly guide adaptive behavior towards survival. Understanding how these decision-making processes and underlying neural computations are orchestrated by the structural components of the brain, from circuits to cells, and ultimately the signaling complex of proteins at synapses, is central to elucidating the mechanisms that shape normal and abnormal brain connectivity, plasticity and behavior. At excitatory synapses, neuroligin-1 (Nlgn1) a postsynaptic cell-adhesion molecule required for the formation of trans-synaptic complexes with presynaptic partners is critical for regulating synapse specification, function and plasticity. Extensive evidence shows Nlgn1 is essential for synaptic transmission and long-term plasticity, but how these signaling processes ultimately regulate components of cognitive behavior is much less understood. Here, employing a comprehensive battery of touchscreen-based cognitive assays, we measured two key decision problems: i) the ability to learn and exploit the associative structure of the environment and ii) the trade-off between potential rewards and costs, or positive and negative utilities associated with available actions. We found that mice lacking Nlgn1 have an intact capacity to acquire complex associative structures and adjust learned associations. However, loss of Nlgn1 alters motivation leading to a reduced willingness to overcome response effort for reward and an increased willingness to exert effort to escape an aversive situation. We suggest Nlgn1 may be important for balancing the weighting on positive and negative utilities in reward-cost trade-off. Our findings identify Nlgn1 is essential for regulating distinct cognitive processes underlying decision-making, providing evidence of a new model for dissociating the computations underlying learning and motivational processing.

neuroscience↗

bioRxiv2019

MicroRNA-210 Knockout Alters Dendritic Density and Behavioural Flexibility

MicroRNAs exert post-transcriptional control over eukaryotic genomes and are integral for regulating complex functions in neurodevelopment, neuroplasticity and cognitive processing. The microRNA-210 (miR-210) is a highly-conserved, hypoxia-regulated miRNA that has been shown to be dysregulated in Alzheimers Disease. We have recently also identified a significant enrichment of neurodegenerative diseases among miR-210 targets within the human transcriptome. To further elucidate the role of miR-210 in neuronal function and cognitive behaviour, we utilised conditional miR-210 knockout mice to characterise miR-210 regulation and function in primary hippocampal neurons and measured visual discrimination and reversal learning using rodent touchscreen assays. We found that miR-210 expression was induced by neuronal activation and loss of neuronal miR-210 increased oxidative metabolism and ROS production as well as dendritic density and branching in vitro. We also found that loss of miR-210 in knockout mice increased behavioural flexibility and reduced perseverative responding during reversal learning which required updating of information and feedback. These data support a conserved, activity-dependent role for miR-210 in cognitive function through modulation of neuronal metabolism.

neuroscience↗

bioRxiv2018

Synaptic combinatorial molecular mechanisms generate repertoires of innate and learned behavior

Although molecular mechanisms underpinning specific behaviors have been described, whether there are mechanisms that orchestrate a behavioral repertoire is unknown. To test if the postsynaptic proteome of excitatory synapses could impart such a mechanism we conducted the largest genetic study of mammalian synapses yet undertaken. A repertoire of sixteen innate and learned behaviors was assessed from 290,850 measures in 55 lines of mutant mice carrying targeted mutations in the principal classes of postsynaptic proteins. Each innate and learned behavior used a different combination of proteins. These combinations were comprised of proteins that amplified or attenuated the magnitude of each behavioral response. All behaviors required proteins found in PSD95 supercomplexes. We show the vertebrate increase in proteome complexity drove an expansion in behavioral repertoires and generated susceptibility to a wide range of diseases. Our results reveal a molecular mechanism that generates a versatile and complex behavioral repertoire that is central to human behavioral disorders.

neuroscience↗