Biology subjects

Deiana, S.

Publications and source records attributed to Deiana, S..

6 recordsLinked to original sources

bioRxiv2025

Social Context Restructures Behavioral Syntax in Mice

The study of social behavior in mice has grown increasingly relevant for unraveling associated brain circuits and advancing the development of treatments for psychiatric symptoms involving social withdrawal or social anxiety. However, a data-driven understanding of behavior and its modulation in solitary and social contexts is lacking. In this study, we employed motion sequencing ("MoSeq") to decompose mouse behaviors into discrete units ("Syllables") and investigate whether--and how--the behavioral repertoire differs between solitary and dyadic (social) settings. Our results reveal that social context significantly modulates a minority (25%) of syllables, containing predominantly stationary and undirected behaviors. Notably, these changes are associated with spatial proximity to another mouse rather than active social contact. Interestingly, a network analysis of syllable transitions shows that context-sensitive syllables exhibit altered network influence, independent of the number of connected syllables, suggesting a regulatory role. Furthermore, syllable composition changes significantly during social contact events with two distinct sequence families governing approach and withdrawal behaviors. However, no unique syllable sequences mapped to specific social interactions. Overall, our findings suggest that a subset of syllables drives contextual behavioral adaptation in mice, potentially facilitating transitions within the broader behavioral repertoire. This highlights the utility of MoSeq in dissecting nuanced, context-dependent behavioral dynamics.

animal behavior and cognition↗

bioRxiv2025

Too little and too much: medial prefrontal functional inhibition impairs early acquisition of operant reversal learning, whereas medial prefrontal disinhibition impairs established serial-reversal performance in rats

Schizophrenia is associated with reduced activation ( hypofrontality) and neural disinhibition (reduced GABAergic inhibition) in the dorsolateral prefrontal cortex (dlPFC), as well as reversal learning deficits. Whilst reversal learning has been strongly linked to the orbitofrontal cortex, its dependence on the primate dlPFC - and its rodent analogue, the medial PFC (mPFC) - is less clear. Nevertheless, we hypothesized that the mPFC may be required for reversal learning if the reversal is demanding. Furthermore, even if the mPFC is not required, mPFC disinhibition may impair reversals, because it may disrupt processing in mPFC projection sites. To test these hypotheses, we combined bi-directional manipulations of mPFC GABAergic inhibition, using intracerebral drug microinfusion and chemogenetic/DREADD methods, with reversal testing on a food-reinforced two-lever discrimination task in rats. First, we induced mPFC functional inhibition and disinhibition, by microinfusion of the GABA-A receptor agonist muscimol or antagonist picrotoxin, respectively, and examined the impact on early reversals (reversals 1-3) and well-established serial reversals (reversal 5 onwards). Using classical performance measures and Bayesian trial-by-trial strategy analysis, we found that mPFC muscimol impaired early, but not serial, reversals, increasing perseveration and impairing exploratory (lose-shift) behavior at reversal 2. In contrast, mPFC picrotoxin impaired serial reversals, reducing exploratory (lose-shift) and exploitative (win-stay) behavior. Second, to inhibit mPFC GABAergic neurons, we expressed the inhibitory DREADD hM4Di in these neurons; chemogenetic mPFC disinhibition by activation of hM4Di also impaired serial reversal learning, primarily disrupting exploitation. Our findings suggest that mPFC hypoactivation and disinhibition disrupt distinct aspects of reversal learning by different mechanisms. Significance statementSchizophrenia is associated with reduced activation ("hypofrontality") and neural disinhibition (reduced GABAergic inhibition) within the prefrontal cortex (PFC). Yet, it is not clear if and how these distinct aspects of prefrontal dysfunction contribute to impaired reversal learning, a key feature of the cognitive inflexibility characterizing schizophrenia. Here, we combined bi-directional manipulations of prefrontal GABAergic inhibition with testing of reversal learning in rats. Increasing prefrontal functional inhibition (i.e., reducing prefrontal activation) selectively impaired early reversals, enhancing perseveration and reducing exploratory (lose-shift) behavior, whereas prefrontal disinhibition disrupted serial reversals, impairing both exploration and exploitation. Our findings suggest that reduced activation and disinhibition of PFC disrupt distinct aspects of reversal learning, by distinct mechanisms.

neuroscience↗

bioRxiv2024

Influence of aversive cue detection sensitivity on extinction in adult male rats

Threat detection prompts reactions classified either as fear (obvious, predictable, immediate threat) or anxiety (ambiguous, sustained, distant threat). Hypervigilance is a state of sensitivity to threatening stimuli and an attentional bias symptomatic of anxiety disorders. In rodents, threat detection can be measured by freezing behaviour and production of ultrasonic vocalisation (USV) alarm calls. The amygdala is classically associated with fear-like responses, whereas the bed nucleus of the stria terminalis (BNST) has been proposed to be preferentially recruited by anxiogenic stimuli. The conditioned responses triggered by aversive cues can be extinguished through repeated exposure of a subject to the threat stimulus but without any aversive reinforcement. The extent of extinction acquisition and consolidation are notedly variable across individuals. It has been reported that NMDA-type glutamate receptor co-agonists, like D-cycloserine, can enhance extinction consolidation. In the experiments herein, the salience of a threat cue was modified to compare the relative activation of the brain vigilance networks to an obvious cue, and to test whether sensitivity to the aversive cue at such a vigilance screen might predict subsequent ability to extinguish conditioned responses. We demonstrated activation of the BNST by a low salience aversive cue. Rats that had the propensity to make alarm ultrasonic vocalisation calls reacted more strongly to aversive cues and had deficits in conditioned freezing extinction. Finally, we demonstrated the potential to enhance extinction consolidation by targeting glycine transmission. Taken together these results demonstrate how threat detection and responses are sensitive to cue salience and can be manipulated by combined pharmacological and behavioural interventions. HIGHLIGHTS-Auditory cue at low salience revealed attentional bias unrelated to maze behaviour -Low salience cue recruited activation of the BNST -Alarm call vocaliser rats had deficit in extinction consolidation -GlyT1 inhibition enhanced extinction consolidation

neuroscience↗

bioRxiv2024

Mesencephalic projections to the nucleus accumbens shell modulate value updating during probabilistic reversal learning

Cognitive flexibility, the capacity to adapt behaviour to changes in the environment, is impaired in a range of brain disorders, including substance use disorder and Parkinsons disease. Putative neural substrates of cognitive flexibility include mesencephalic pathways to the ventral striatum (VS) and dorsomedial striatum (DMS), hypothesised to encode learning signals needed to maximize rewarded outcomes during decision-making. However, it is unclear whether mesencephalic projections to the ventral and dorsal striatum are distinct in their contribution to flexible reward-related learning. Here, rats acquired a two-choice spatial probabilistic reversal learning (PRL) task, reinforced on an 80%:20% basis, that assessed the flexibility of behaviour to repeated reversals of response-outcome contingencies. We report that optogenetic stimulation of projections from the ventral tegmental area (VTA) to the nucleus accumbens shell (NAcbS) in the VS significantly impaired reversal learning when optical stimulation was temporally aligned with negative feedback (i.e., reward omission). Moreover, the exploitation-exploration parameter, {beta}, was increased (indicating greater exploitation of information) when this pathway was optogenetically stimulated after a spurious loss (i.e. an incorrect (20%) response at the 80% reinforrced location) compared to after a spurious win (i.e. a correct (20%) response at the 20% reinforced location). VTA [->] NAcbS stimulation during other phases of the behavioural task was without effect. Optogenetic stimulation of projection neurons from the substantia nigra (SN) to the DMS, aligned either with reward receipt or omission or prior to making a choice, had no effect on reversal learning. These findings are consistent with the notion that enhanced activity in VTA [->] NAcbS projections leads to maladaptive perseveration as a consequence of an inappropriate bias to exploitation via positive reinforcement.

animal behavior and cognition↗

bioRxiv2024

Long-term adaptation of prefrontal circuits in a mouse model of NMDAR hypofunction

Pharmacological approaches to induce N-methyl-D-aspartate receptor (NMDAR) hypofunction have been intensively used to understand the aetiology and pathophysiology of schizophrenia. Yet, the precise cellular and molecular mechanisms that relate to brain network dysfunction remain largely unknown. Here, we used a set of complementary approaches to assess the functional network abnormalities present in mice that underwent a 7-day subchronic phencyclidine (PCP 10mg/kg, subcutaneously, once daily) treatment. Our data revealed that pharmacological intervention with PCP affected cognitive performance and auditory evoked gamma oscillations in the prefrontal cortex (PFC) mimicking endophenotypes of some schizophrenia patients. We further assessed PFC cellular function and identified altered neuronal intrinsic membrane properties, reduced parvalbumin (PV) immunostaining and diminished inhibition onto L5 PFC pyramidal cells. A decrease in the strength of optogenetically-evoked glutamatergic current at the ventral hippocampus (HPC) to PFC synapse was also demonstrated, along with a weaker shunt of excitatory transmission by local PFC interneurons. On a macrocircuit level, functional ultrasound measurements indicated compromised functional connectivity within several brain regions particularly involving PFC and frontostriatal circuits. Herein, we reproduced a panel of schizophrenia endophenotypes induced by subchronic PCP application in mice. We further recapitulated electrophysiological signatures associated with schizophrenia and provided an anatomical reference to critical elements in the brain circuitry. Together, our findings contribute to a better understanding of the physiological underpinnings of deficits induced by subchronic NMDAR antagonist regimes and provide a test system for characterization of pharmacological compounds. HighlightsO_LISubchronic PCP treatment alters cognitive performance and evoked gamma synchronization in the prefrontal cortex. C_LIO_LISubchronic PCP reduces number of parvalbumin-positive boutons and inhibitory synaptic transmission onto pyramidal neurons in layer 5/6 of the prelimbic cortex. C_LIO_LISubchronic PCP reduces the strength of ventral hippocampal inputs to the medial prefrontal cortex. C_LIO_LIFrontostriatal circuits show robust dysconnectivity after subchronic PCP treatment. Abstract C_LI

neuroscience↗

bioRxiv2022

Reactivity to conditioned threat cues is distinct from exploratory drive in the elevated plus-maze.

Fear and anxiety are adaptive states that allow humans and animals alike to respond appropriately to threatening cues in their environment. Commonly used tasks for studying behaviour akin to fear and anxiety in rodent models are pavlovian threat conditioning and the elevated plus maze (EPM) respectively. In threat conditioning the rodents learn to associate an aversive event with a specific stimulus or context. The learnt association between the two stimuli (the memory) can then be recalled by re-exposing the subject to the conditioned stimulus. The elevated plus maze is argued to measure the agoraphobic avoidance of the brightly lit open maze arms in crepuscular rodents. These two tasks have been used extensively, yet research into whether they interact is scarce. We investigated whether recall of an aversive memory, across contextual, odour or auditory modalities, would potentiate anxiety-like behaviour in the elevated plus maze. The data did not support that memory recall, even over a series of timepoints, could influence EPM behaviour. Furthermore, there was no correlation between EPM behaviour and conditioned freezing in independent cohorts tested in the EPM before or after auditory threat conditioning. Further analysis found the production of 22kHz ultrasonic vocalisations revealed the strongest responders to a conditioned threat cue. These results are of particular importance for consideration when using the EPM and threat conditioning to identify individual differences, and the possibility to use the tasks in batteries of tests without cross-task interference.

neuroscience↗