Novelty Discrimination Research Articles

Automated analysis of a novel object recognition test in mice using image processing and machine learning

The novel object recognition test (NORT) is one of the most commonly employed behavioral tests in experimental animals designed to evaluate an animal's interest in and recognition of novelty. However, manual procedures, which rely on researchers’ observations, prevent high throughput analysis. In this study, we developed an automated analysis method for NORT utilizing machine learning-assisted exploratory behavior detection. We recorded the exploratory behavior of the mice using a video camera. The coordinates of the mouse nose and tail base in recorded video files were detected using a pre-trained machine learning model, DeepLabCut. Each video was then segmented into frame images, which were categorized into "exploratory,” or "non-exploratory" frames based on manual observation. Mouse feature vectors were calculated as vectors from the nose to the vertices of the object and were utilized for SVM training. The trained SVM effectively detected exploratory behaviors, showing a strong correlation with human observer assessments. Upon application to NORT, the duration of mouse exploratory behavior towards objects predicted by the SVM exhibited a significant correlation with the assessments made by human observers. The novelty discrimination index derived from the SVM predictions also aligned well with that from human observations.

R-Baclofen Treatment Corrects Autistic-like Behavioral Deficits in the RjIbm(m):FH Fawn-Hooded Rat Strain.

The Fawn-hooded rat has long been used as a model for various peripheral and central disorders and the data available indicate that the social behavior of this strain may be compromised. However, a thorough description of the Fawn-hooded rat is unavailable in this regard. The objective of the present study was to investigate various aspects of the Fawn-hooded rat's social behavior in depth. Our results show that several facets of socio-communicational behavior are impaired in the RjIbm(m):FH strain, including defective ultrasonic vocalizations in pups upon maternal deprivation, reduced social play in adolescence and impaired social novelty discrimination in adulthood. In addition, Fawn-hooded rats exhibited heightened tactile sensitivity and hyperactivity. The defects observed were comparable to those induced by prenatal valproate exposure, a widely utilized model of autism spectrum disorder. Further on, the pro-social drug R-baclofen (0.25-1 mg/kg) reversed the autistic-like defects observed in Fawn-hooded rats, specifically the deficiency in ultrasonic vocalization, tactile sensitivity and social novelty discrimination endpoints. In conclusion, the asocial, hypersensitive and hyperactive phenotype as well as the responsivity to R-baclofen indicate this variant of the Fawn-hooded rat strain may serve as a model of autism spectrum disorder and could be useful in the identification of novel drug candidates.

Social Isolation Induces Changes in the Monoaminergic Signalling in the Rat Medial Prefrontal Cortex.

(1) Background: The effects of short-term social isolation during adulthood have not yet been fully established in rats behaviourally, and not at all transcriptomically in the medial prefrontal cortex (mPFC). (2) Methods: We measured the behavioural effects of housing adult male rats in pairs or alone for 10 days. We also used RNA sequencing to measure the accompanying gene expression alterations in the mPFC of male rats. (3) Results: The isolated animals exhibited reduced sociability and social novelty preference, but increased social interaction. There was no change in their aggression, anxiety, or depression-like activity. Transcriptomic analysis revealed a differential expression of 46 genes between the groups. The KEGG pathway analysis showed that differentially expressed genes are involved in neuroactive ligand-receptor interactions, particularly in the dopaminergic and peptidergic systems, and addiction. Subsequent validation confirmed the decreased level of three altered genes: regulator of G protein signalling 9 (Rgs9), serotonin receptor 2c (Htr2c), and Prodynorphin (Pdyn), which are involved in dopaminergic, serotonergic, and peptidergic function, respectively. Antagonizing Htr2c confirmed its role in social novelty discrimination. (4) Conclusions: Social homeostatic regulations include monoaminergic and peptidergic systems of the mPFC.

Role of dopamine neurons in familiarity.

Dopamine neurons signal the salience of environmental stimuli and influence learning, although it is less clear if these neurons also determine the salience of memories. Ventral tegmental area (VTA) dopamine neurons increase their firing in the presence of new objects and reduce it upon repeated, inconsequential exposures, marking the shift from novelty to familiarity. This study investigates how dopamine neuron activity during repeated familiar object exposure affects an animal's preference for new objects in a subsequent novel object recognition (NOR) test. We hypothesize that a single familiarization session will not sufficiently lower dopamine activity, such that the memory of a familiar object remains salient, leading to equal exploration of familiar and novel objects and weaker NOR discrimination. In contrast, multiple familiarization sessions likely suppress dopamine activity more effectively, reducing the salience of the familiar object and enhancing subsequent novelty discrimination. Our experiments in mice indicated that multiple familiarization sessions reduce VTA dopamine neuron activation, as measured by c-Fos expression, and enhance novelty discrimination compared with a single familiarization session. Dopamine neurons that show responsiveness to novelty were primarily located in the paranigral nucleus of the VTA and expressed vesicular glutamate transporter 2 transcripts, marking them as dopamine-glutamate neurons. Chemogenetic inhibition of dopamine neurons during a single session paralleled the effects of multiple sessions, improving NOR. These findings suggest that a critical role of dopamine neurons during the transition from novelty to familiarity is to modulate the salience of an object's memory.

Impairments in the early consolidation of spatial memories via group II mGluR agonism in the mammillary bodies

mGluR2 receptors are widely expressed in limbic brain regions associated with memory, including the hippocampal formation, retrosplenial and frontal cortices, as well as subcortical regions including the mammillary bodies. mGluR2/3 agonists have been proposed as potential therapeutics for neurological and psychiatric disorders, however, there is still little known about the role of these receptors in cognitive processes, including memory consolidation. To address this, we assessed the effect of the mGluR2/3 agonist, eglumetad, on spatial memory consolidation in both mice and rats. Using the novel place preference paradigm, we found that post-sample injections of eglumetad impaired subsequent spatial discrimination when tested 6 h later. Using the immediate early gene c-fos as a marker of neural activity, we showed that eglumetad injections reduced activity in a network of limbic brain regions including the hippocampus and mammillary bodies. To determine whether the systemic effects could be replicated with more targeted manipulations, we performed post-sample infusions of the mGluR2/3 agonist 2R,4R-APDC into the mammillary bodies. This impaired novelty discrimination on a place preference task and an object-in-place task, again highlighting the role of mGluR2/3 transmission in memory consolidation and demonstrating the crucial involvement of the mammillary bodies in post-encoding processing of spatial information.

Insulin-like growth factor 2 (IGF-2) rescues social deficits in NLG3-/y mouse model of ASDs.

Autism spectrum disorders (ASDs) comprise developmental disabilities characterized by impairments of social interaction and repetitive behavior, often associated with cognitive deficits. There is no current treatment that can ameliorate most of the ASDs symptomatology; thus, identifying novel therapies is urgently needed. Here, we used the Neuroligin 3 knockout mouse (NLG3-/y), a model that recapitulates the social deficits reported in ASDs patients, to test the effects of systemic administration of IGF-2, a polypeptide that crosses the blood-brain barrier and acts as a cognitive enhancer. We show that systemic IGF-2 treatment reverses the typical defects in social interaction and social novelty discrimination reflective of ASDs-like phenotypes. This effect was not accompanied by any change in spontaneous glutamatergic synaptic transmission in CA2 hippocampal region, a mechanism found to be crucial for social novelty discrimination. However, in both NLG3+/y and NLG3-/y mice IGF-2 increased cell excitability. Although further investigation is needed to clarify the cellular and molecular mechanisms underpinning IGF-2 effect on social behavior, our findings highlight IGF-2 as a potential pharmacological tool for the treatment of social dysfunctions associated with ASDs.

Social Interaction in Adolescent Rats with Neonatal Ethanol Exposure: Impact of Sex and CE-123, a Selective Dopamine Reuptake Inhibitor.

Children with fetal alcohol spectrum disorders (FASDs) demonstrate deficits in social functioning that contribute to early withdrawal from school and delinquency, as well as the development of anxiety and depression. Dopamine is involved in reward, motivation, and social behavior. Thus, we evaluated whether neonatal ethanol exposure (in an animal model of FASDs) has an impact on social recognition memory using the three-chamber social novelty discrimination test during early and middle adolescence in male and female rats, and whether the modafinil analog, the novel atypical dopamine reuptake inhibitor CE-123, can modify this effect. Our study shows that male and female rats neonatally exposed to ethanol exhibited sex- and age-dependent deficits in social novelty discrimination in early (male) and middle (female) adolescence. These deficits were specific to the social domain and not simply due to more general deficits in learning and memory because these animals did not exhibit changes in short-term recognition memory in the novel object recognition task. Furthermore, early-adolescent male rats that were neonatally exposed to ethanol did not show changes in the anxiety index but demonstrated an increase in locomotor activity. Chronic treatment with CE-123, however, prevented the appearance of these social deficits. In the hippocampus of adolescent rats, CE-123 increased BDNF and decreased its signal transduction TrkB receptor expression level in ethanol-exposed animals during development, suggesting an increase in neuroplasticity. Thus, selective dopamine reuptake inhibitors, such as CE-123, represent interesting drug candidates for the treatment of deficits in social behavior in adolescent individuals with FASDs.

Alterations in a cross-hemispheric circuit associates with novelty discrimination deficits in mouse models of neurodegeneration

A major pathological hallmark of neurodegenerative diseases, including Alzheimer's, is a significant reduction in the white matter connecting the two cerebral hemispheres, as well as in the correlated activity between anatomically corresponding bilateral brain areas. However, the underlying circuit mechanisms and the cognitive relevance of cross-hemispheric (CH) communication remain poorly understood. Here, we show that novelty discrimination behavior activates CH neurons and enhances homotopic synchronized neural oscillations in the visual cortex. CH neurons provide excitatory drive required for synchronous neural oscillations between hemispheres, and unilateral inhibition of the CH circuit is sufficient to impair synchronous oscillations and novelty discrimination behavior. In the 5XFAD and Tau P301S mouse models, CH communication is altered, and novelty discrimination is impaired. These data reveal a hitherto uncharacterized CH circuit in the visual cortex, establishing a causal link between this circuit and novelty discrimination behavior and highlighting its impairment in mouse models of neurodegeneration.

Age-related loss of recognition memory and its correlation with hippocampal and perirhinal cortex changes in female Sprague Dawley rats

Ageing is associated with impaired performance in recognition memory, a process that consists of the discrimination of familiar and novel stimuli. Previous studies have shown the impact of ageing on object recognition memories. However, the early stages of memory impairment remain unknown. To fill this gap, we aimed at evaluating the ability of young (Y), middle-aged (MA), and senile (S) female Sprague-Dawley rats to retain 24 h long-term recognition memory. The MA cohort was included to characterise early memory deficits under two behavioural paradigms based on spontaneous location recognition (SLR) and spontaneous object recognition (SOR) tasks. In the SLR task, there was a markedly diminished novel discrimination capacity in the MA and S rats compared with the Y ones. In the SOR task, S rats evidenced a deterioration in novelty discrimination, while MA rats partially preserved the capacity to distinguish the new stimulus as compared with Y rats. Regarding early changes from MA to S rats, immunohistochemistry showed a marked decrease in the number and diameter of adult-born immature neurons in the Dentate Gyrus (DG) with a positive correlation with behavioural performance in the SLR task. Furthermore, we found a slight reduction in CA3 mature neurons and a decrease in the number of total microglia in the perirhinal cortex (Prh) in MA and S rats as compared with Y rats. As regards changes that were only observed in S rats, we found an increase in the number of total and reactive microglia in CA3 and a reduction in the number of total microglia in the DG. We conclude that spatial discrimination capacity could be affected earlier than feature discrimination capacity. We suggest that early depletion of neurogenesis in MA rats is involved in object location recognition deficits, whereas the disruption of microglial homeostasis in the Prh could be associated with object feature discrimination capacity.

Exposure to anesthetics in neonatal period of the rats impairs their sociality and social novelty discrimination behavior via disruption of dopaminergic system

Exposure to anesthetics in neonatal period of the rats impairs their sociality and social novelty discrimination behavior via disruption of dopaminergic system

Acute hypoxia exposure following prenatal stress impairs hippocampus and novelty-seeking behavior in adolescent rats.

The present study aimed to investigate the effects of acute hypoxia exposure following prenatal stress on the novelty-seeking behavior and hippocampus of adolescent rats. The offspring were divided into prenatal stress (PS) and non-stress (NS) groups. Both groups were exposed to hypoxia on postnatal day 10 (P10) while control groups were undisturbed. Novel object recognition task was performed in each group. Next, brains were collected to examine hippocampus via immunohistochemical and biochemical studies on postnatal day 35 (P35). PS decreased novelty discrimination and synaptophysin (SYN) expressions in both CA1 and CA3 of the hypoxia group prominently (p < 0.05). Nestin-expressing cells were reduced while vascular endothelial growth factor (VEGF) expression was enhanced in the subgranular zone (SGZ) of PS-hypoxia group (p < 0.05). VEGF enhancement triggered angiogenesis in the CA1 and CA3 significantly (p < 0.05). PS also increased thiobarbituric acid reactive substances (TBARS) levels in the hypoxia group as a result of oxidative stress (p < 0.05). These findings demonstrated that PS exacerbates neurodevelopmental deficits in the hippocampus of acute hypoxia-induced offspring in adolescence.

Septal cholinergic input to CA2 hippocampal region controls social novelty discrimination via nicotinic receptor-mediated disinhibition.

Acetylcholine (ACh), released in the hippocampus from fibers originating in the medial septum/diagonal band of Broca (MSDB) complex, is crucial for learning and memory. The CA2 region of the hippocampus has received increasing attention in the context of social memory. However, the contribution of ACh to this process remains unclear. Here, we show that in mice, ACh controls social memory. Specifically, MSDB cholinergic neurons inhibition impairs social novelty discrimination, meaning the propensity of a mouse to interact with a novel rather than a familiar conspecific. This effect is mimicked by a selective antagonist of nicotinic AChRs delivered in CA2. Ex vivo recordings from hippocampal slices provide insight into the underlying mechanism, as activation of nAChRs by nicotine increases the excitatory drive to CA2 principal cells via disinhibition. In line with this observation, optogenetic activation of cholinergic neurons in MSDB increases the firing of CA2 principal cells in vivo. These results point to nAChRs as essential players in social novelty discrimination by controlling inhibition in the CA2 region.

Hippocampus-Prefrontal Coupling Regulates Recognition Memory for Novelty Discrimination.

Recognition memory provides the ability to distinguish familiar from novel objects and places, and is important for recording and updating events to guide appropriate behavior. The hippocampus (HPC) and medial prefrontal cortex (mPFC) have both been implicated in recognition memory, but the nature of HPC-mPFC interactions, and its impact on local circuits in mediating this process is not known. Here we show that novelty discrimination is accompanied with higher theta activity (4-10 Hz) and increased c-Fos expression in both these regions. Moreover, theta oscillations were highly coupled between the HPC and mPFC during recognition memory retrieval for novelty discrimination, with the HPC leading the mPFC, but not during initial learning. Principal neurons and interneurons in the mPFC responded more strongly during recognition memory retrieval compared with learning. Optogenetic silencing of HPC input to the mPFC disrupted coupled theta activity between these two structures, as well as the animals' (male Sprague Dawley rats) ability to differentiate novel from familiar objects. These results reveal a key role of monosynaptic connections between the HPC and mPFC in novelty discrimination via theta coupling and identify neural populations that underlie this recognition memory-guided behavior.SIGNIFICANCE STATEMENT Many memory processes are highly dependent on the interregional communication between the HPC and mPFC via neural oscillations. However, how these two brain regions coordinate their oscillatory activity to engage local neural populations to mediate recognition memory for novelty discrimination is poorly understood. This study revealed that the HPC and mPFC theta oscillations and their temporal coupling is correlated with recognition memory-guided behavior. During novel object recognition, the HPC drives mPFC interneurons to effectively reduce the activity of principal neurons. This study provides the first evidence for the requirement of the HPC-mPFC pathway to mediate recognition memory for novelty discrimination and describes a mechanism for how this memory is regulated.

Positive modulation of α5GABAA receptors leads to dichotomous effects in rats on memory pattern and GABRA5 expression in prefrontal cortex and hippocampus

Positive allosteric modulators (PAMs) of α5GABAA receptors (α5GABAARs) are emerging as potential therapeutics for a range of neuropsychiatric disorders. However, their role in memory processing of healthy animals is not sufficiently examined. We tested the effects of MP-III-022 (1 mg/kg, 2.5 mg/kg and 10 mg/kg), a PAM known to be selective for α5GABAARs and devoid of prominent side-effects, in different behavioral paradigms (Morris water maze, novel object recognition test and social novelty discrimination) and on GABRA5 expression in Wistar rats, 30 min and 24 h after intraperitoneal treatment administration. The lowest dose tested worsened short-term object memory. The same dose, administered two times in a span of 24 h, improved spatial and impaired object and, at a trend level, social memory. The highest dose had a detrimental effect on all types of long-term memory (object memory at a trend level) and short-term spatial memory, but improved short-term object and social memory. Distinct sets of expression changes were detected in both prefrontal cortex and two regions of the hippocampus, but the latter ones could be assessed as more consequential. An increase of GABRA5 mRNA in CA2 occurred in parallel with improvement of object and social, but impairment of spatial memory, while the opposite happened with a trend level change in CA1. Our study demonstrates the variability of the roles of the α5GABAAR based on its level of expression and localization, in dependence on the type and protocol of cognitive tasks, as well as the respective timing of pharmacological modulation and testing.

Long-term associative memory in rats: Effects of familiarization period in object-place-context recognition test.

Spontaneous recognition tests, which utilize rodents' innate tendency to explore novelty, can evaluate not only simple non-associative recognition memory but also more complex associative memory in animals. In the present study, we investigated whether the length of the object familiarization period (sample phase) improved subsequent novelty discrimination in the spontaneous object, place, and object-place-context (OPC) recognition tests in rats. In the OPC recognition test, rats showed a significant novelty preference only when the familiarization period was 30 min but not when it was 5 min or 15 min. In addition, repeated 30-min familiarization periods extended the significant novelty preference to 72 hours. However, the rats exhibited a successful discrimination between the stayed and replaced objects under 15 min and 30 min familiarization period conditions in the place recognition test and between the novel and familiar objects under all conditions of 5, 15 and 30 min in the object recognition test. Our results suggest that the extension of the familiarization period improves performance in the spontaneous recognition paradigms, and a longer familiarization period is necessary for long-term associative recognition memory than for non-associative memory.

Cross-Hemispheric Circuit Dysfunction Impairs Novelty Discrimination in Alzheimer's Disease Mice

SUMMARYA clinical hallmark of Alzheimer’s disease is significant reductions in the white matter connecting the two cerebral hemispheres, as well as in the correlated activity between anatomically corresponding bilateral brain areas. However, the underlying circuit mechanisms and the cognitive relevance of cross-hemispheric communication remain poorly studied. Here, we show that novelty discrimination behavior activated cross-hemispheric neurons and enhanced homotopic synchronized gamma oscillations in the visual cortex. Cross-hemispheric neurons provide excitatory drive required for synchronous gamma oscillations between hemispheres and unilateral inhibition of the cross-hemispheric circuit is sufficient to impair behavior. In the 5XFAD mouse model of Alzheimer’s disease, cross-hemispheric communication is compromised and novelty discrimination is impaired; a deficit rescued by gamma sensory stimulation. These data establish a causal link between a cross-hemispheric circuit and behavior and highlight its impairment in Alzheimer’s disease mice.

Increased Endocannabinoid Signaling Reduces Social Motivation in Intact Rats and Does Not Affect Animals Submitted to Early-Life Seizures.

The early life status epilepticus (SE) causes high anxiety and chronic socialization abnormalities, revealed by a low preference for social novelty and deficit in social discrimination. This study investigated the involvement of the endocannabinoid system on the sociability in this model, due to its role in social motivation regulation. Male Wistar rats at postnatal day 9 were subjected to pilocarpine-induced neonatal SE and controls received saline. From P60 the groups received vehicle or JZL195 2 h before each behavioral test to increase endocannabinoids availability. In the sociability test, animals subjected to neonatal SE exhibited impaired sociability, characterized by social discrimination deficit, which was unaffected by the JZL195 treatment. In contrast, JZL195-treated control rats showed low sociability and impaired social discrimination. The negative impact of JZL195 over the sociability in control rats and the lack of effect in animals subjected to neonatal SE was confirmed in the social memory paradigm. In this paradigm, as expected for vehicle-treated control rats, the investigation toward the same social stimulus decreased with the sequential exposition and increased toward a novel stimulus. In animals subjected to neonatal SE, regardless of the treatment, as well as in JZL195-treated control rats, the investigation toward the same social stimulus was significantly reduced with no improvement toward a novel stimulus. Concerning the locomotion, the JZL195 increased it only in control rats. After behavioral tests, brain tissues of untreated animals were used for CB1 receptor quantification by Elisa and for gene expression by RT-PCR: no difference between control and experimental animals was noticed. The results reinforce the evidence that the early SE causes chronic socialization abnormalities, revealed by the low social interest for novelty and impaired social discrimination. The dual FAAH/MAGL inhibitor (JZL195) administration before the social encounter impaired the social interaction in intact rats with no effect in animals subjected to early-life seizures.

TLR2 deficiency attenuated chronic intermittent hypoxia-induced neurocognitive deficits

Chronic intermittent hypoxia (CIH) is the main symptom of obstructive sleep apnea syndrome (OSAS) and causes neural damage and cognitive deficits via neuroinflammation. Toll-like receptors (TLRs), especially TLR2, play an important role in neuroinflammation. However, the mechanisms by which TLR2 participates in CIH-induced cognitive deficits remain unclear. In this study, wild-type (WT) and TLR2 knock out (KO) mice were exposed to CIH for 8 weeks, and their social novelty discrimination, spatial learning and memory were severely compromised. Additionally, seriously damaged neurons and abnormally activated glia were observed in the CA1 and dentate gyrus (DG) areas of the hippocampus. Mechanistically, knocking out the TLR2 gene significantly alleviated these pathological changes and improved the behavioral performance. Together, these findings demonstrate that the TLR2-MyD88 signaling pathway might play an important role in CIH-induced cognitive deficits.

Activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) regulates anxiety- and novelty-related behaviors.

The activity-regulated cytoskeleton-associated protein (Arc, also known as Arg3.1) regulates glutamatergic synapse plasticity and has been linked to neuropsychiatric illness; however, its role in behaviors associated with mood and anxiety disorders remains unclear. We find that stress upregulates Arc expression in the adult mouse nucleus accumbens (NAc)-a brain region implicated in mood and anxiety behaviors. Global Arc knockout mice have altered AMPAR-subunit surface levels in the adult NAc, and the Arc-deficient mice show reductions in anxiety-like behavior, deficits in social novelty preference, and antidepressive-like behavior. Viral-mediated expression of Arc in the adult NAc of male, global Arc KO mice restores normal levels of anxiety-like behavior in the elevated plus maze (EPM). Consistent with this finding, viral-mediated reduction of Arc in the adult NAc reduces anxiety-like behavior in male, but not female, mice in the EPM. NAc-specific reduction of Arc also produced significant deficits in both object and social novelty preference tasks. Together our findings indicate that Arc is essential for regulating normal mood- and anxiety-related behaviors and novelty discrimination, and that Arc's function within the adult NAc contributes to these behavioral effects.

P.2.005 - Knock-down of G protein-coupled receptor 88 in the striatum reduces psychiatric symptoms in a rat non-motor model of Parkinson’s disease

Although Parkinson's disease (PD) is commonly defined as a progressive motor disorder, it entails many psychiatric non-motor symptoms (NMS) such as depression and cognitive alterations that are irresponsive to L-DOPA treatment and are thus in need of new and more specific targets for their treatment. This underpins interest in Gpr88, a brain-specific orphan G-protein coupled receptor whose expression in the striatal medium spiny neurons is modulated by L-DOPA as well as 6-hydroxydopamine (6OHDA) lesions [1]. Knock-down (KD) of Gpr88 in the ventral striatum (STR) normalizes motor and cognitive alterations in a rat model of psychosis [2], so in this study, we evaluated the impact of Gpr88-KD on depressed mood, sensorimotor gating and social recognition in a model of psychiatric NMS of PD. Partial lesions reproducing several psychiatric symptoms of PD were induced by bilateral stereotaxic injections of 6OHDA (12µg/hemisphere), or control saline, in the dorsolateral STR of rats. Then, Gpr88 was knocked-down using a lentiviral vector co-expressing the emerald Green Fluorescent Protein (emGFP) marker and either a specific (miR-Gpr88) or control (miR-neg) microRNA. These vectors were bilaterally injected into either the ventral (v), dorsomedial (dm), or dorsolateral (dl) STR (2 or 6µl/hemisphere, in the ventral or dorsal regions respectively). The rats were then tested for: depression with the forced swim test (FST); sensorimotor filtering with the Prepulse Inhibition test (PPI, prepulses ranging from 70-80dB and pulse = 110dB); and social recognition with the social novelty discrimination (SND) test, which measures discrimination of a novel from a familiar juvenile rat (score ≥ 3 in controls). The efficacy of the 6-OHDA lesion was quantified by the loss of Tyrosine Hydroxylase (TH) immunofluorescence, and the lentiviral transduction extent and location was validated by emGFP detection. Statistical analyses were performed using one-way ANOVA followed by Bonferroni corrections. Results are expressed as means ± SEM. The 6-OHDA lesion was limited to the dlSTR where it induced a significant loss of TH immunoreactivity (-57.10% ± 4.23, p Taken together, these results indicate that striatal Gpr88 KD moderates striatal dopamine depletion related alterations in mood, sensory motor gating and social discrimination in a model of NMS of PD. This study thus highlights the relevance of GPR88 as a potential target for the control of the psychiatric symptoms of PD, and possibly of other neuropsychiatric diseases.