Small lesions of the dorsal or ventral hippocampus subregions are associated with distinct impairments in working memory and reference memory retrieval, and combining them attenuates the acquisition rate of spatial reference memory.

The importance of the hippocampus in spatial learning is well established, but the precise relative contributions by the dorsal (septal) and ventral (temporal) subregions remain unresolved. One debate revolves around the extent to which the ventral hippocampus contributes to spatial navigation and learning. Here, separate small subtotal lesions of dorsal hippocampus or ventral hippocampus alone (destroying 18.9 and 28.5% of total hippocampal volume, respectively) spared reference memory acquisition in the water maze. By contrast, combining the two subtotal lesions significantly reduced the rate of acquisition across days. This constitutes evidence for synergistic integration between dorsal and ventral hippocampus in mice. Evidence that ventral hippocampus contributes to spatial/navigation learning also emerged early on during the retention probe test as search preference was reduced in mice with ventral lesions alone or combined lesions. The small ventral lesions also led to anxiolysis in the elevated plus maze and over-generalization of the conditioned freezing response to a neutral context. Similar effects of comparable magnitudes were seen in mice with combined lesions, suggesting that they were largely due to the small ventral damage. By contrast, small dorsal lesions were uniquely associated with a severe spatial working memory deficit in the water maze. Taken together, both dorsal and ventral poles of the hippocampus contribute to efficient spatial navigation in mice: While the integrity of dorsal hippocampus is necessary for spatial working memory, the acquisition and retrieval of spatial reference memory are modulated by the ventral hippocampus. Although the impairments following ventral damage (alone or in combination with dorsal damage) were less substantial, a wider spectrum of spatial learning, including context conditioning, was implicated. Our results encourage the search for integrative mechanism between dorsal and ventral hippocampus in spatial learning. Candidate neural substrates may include dorsoventral longitudinal connections and reciprocal modulation via overlapping polysynaptic networks beyond hippocampus.

The Protective Impact of Telemedicine on Persons With Dementia and Their Caregivers During the COVID-19 Pandemic.

OBJECTIVES: Social distancing under the COVID-19 pandemic has restricted access to community services for older adults with neurocognitive disorder (NCD) and their caregivers. Telehealth is a viable alternative to face-to-face service delivery. Telephone calls alone, however, may be insufficient. Here, we evaluated whether supplementary telehealth via video-conferencing platforms could bring additional benefits to care-recipient with NCD and their spousal caregivers at home. PARTICIPANTS: Sixty older adults NCD-and-caregiver dyads were recruited through an activity center. DESIGN, INTERVENTION: The impact of additional services delivered to both care-recipient and caregiver through video conference (n = 30) was compared with telehealth targeted at caregivers by telephone only (n = 30), over 4 weeks in a pretest-post-test design. Interviews and questionnaires were conducted at baseline and study's end. MEASUREMENTS, RESULTS: Supplementary telemedicine had averted the deterioration in the Montreal Cognitive Assessment evident in the telephone-only group (ηp2 = 0.50). It also reversed the falling trend in quality of life observed in the telephone only group (QoL-AD, ηp2 = 0.23). Varying degrees of improvements in physical and mental health (Short-Form 36 v2), perceived burden (Zarit Burden Interview Scale) and self-efficacy (Revised Caregiving Self-Efficacy Scale) were observed among caregivers in the video-conferencing group, which were absent in the telephone-only group (ηp2 = 0.23-0.51). CONCLUSION: Telemedicine by video conference was associated with improved resilience and wellbeing to both people with NCD and their caregivers at home. The benefits were visible already after 4 weeks and unmatched by telephone alone. Video conference as the modus operandi of telehmedicine beyond the context of pandemic-related social distancing should be considered.

Exosomes in Inflammation and Inflammatory Disease.

Exosomes are a subset of extracellular vesicles released by all cell types and involved in local and systemic intercellular communication. In the past decade, research into exosomes has swelled as their important role in the mediation of health and disease has been increasingly established and acknowledged. Exosomes carry a diverse range of cargo including proteins, nucleic acids, and lipids derived from their parental cell that, when delivered to the recipient cell, can confer pathogenic or therapeutic effects through modulation of immunity and inflammation. In this review, the role of exosomes on mediation of immune and inflammatory responses, and their participation in diseases with a significant inflammatory component is discussed. The considerable potential for exosomes in therapy and diagnosis of inflammatory diseases is also highlighted.

Individual difference in prepulse inhibition does not predict spatial learning and memory performance in C57BL/6 mice.

The startle reflex to an intense acoustic pulse stimulus is attenuated if the pulse stimulus is shortly preceded by a weak non-startling prepulse stimulus. This attenuation of the startle reflex represents a form of pre-attentional sensory gating known as prepulse inhibition (PPI). Although PPI does not require learning, its expression is regulated by higher cognitive processes. PPI deficits have been detected in several psychiatric conditions including schizophrenia where they co-exist with cognitive deficits. A potential link between PPI expression and cognitive performance has therefore been suggested such that poor PPI may predict, or may be mechanistically linked to, overt cognitive impairments. A positive relationship between PPI and strategy formation, planning efficiency, and execution speed has been observed in healthy humans. However, parallel studies in healthy animals are rare. It thus remains unclear what cognitive domains may be associated with, or orthogonal to, sensory gating in the form of PPI in healthy animals. The present study evaluated a potential link between the magnitude of PPI and spatial memory performance by comparing two subgroups of animals differing substantially in baseline PPI expression (low-PPI vs high-PPI) within a homogenous cohort of 100 male adult C57BL/6 mice. Assessment of spatial reference memory in the Morris water maze and spatial recognition memory in the Y-maze failed to reveal any difference between low-PPI and high-PPI subjects. These negative findings contrast with our previous reports that individual difference in PPI correlated with sustained attention and working memory performance in C57BL/6 mice.

Environmental enrichment eliminates the anxiety phenotypes in a triple transgenic mouse model of Alzheimer's disease.

Although the impacts of environmental enrichment (EE) in several genetic models of Alzheimer's disease (AD) have been documented, the focus has remained predominantly on cognition. Few have investigated the expression of emotional phenotypes that mimic the notable affective features in AD. Here, we studied the interaction between EE and the coexpression of three genetic risk factors (mutations) for AD. In a longitudinal design, 3×Tg-AD mutants and wild type controls were compared at 6-7 months and subsequently at 12-13 months of age. Under standard housing, phenotypes of heightened anxiety levels were identified in the 3×Tg-AD mice in the elevated plus maze and open-field tests. Such trait differences between genotypes were substantially diminished under EE housing, which was attributable to the anxiolytic impact of EE on the mutant mice as much as the anxiogenic impact of EE on the wild type mice. In contrast, the phenotypes in learned fear were not significantly modified by EE in the tests of Pavlovian freezing and conditioned active avoidance conducted at either age. Rearing under EE thus has uncovered a novel distinction between innate and acquired expressions of fear response in the 3×Tg-AD mouse model that might be relevant to the mental health management of AD.

Forebrain glycine transporter 1 deletion enhances sensitivity to CS-US discontiguity in classical conditioning.

The deletion of glycine transporter 1 (GlyT1) in forebrain neurons can apparently strengthen Pavlovian aversive conditioning, but this phenotype is not expressed if conditioning followed non-reinforced pre-exposures of the to-be-conditioned stimulus (CS). To examine whether GlyT1 disruption may only enhance aversive associative learning under conditions that most favour the formation of CS-US excitatory link, we evaluated the impact of GlyT1 disruption on the trace conditioning procedure whereby a trace interval between a tone CS and a shock US was introduced during conditioning. CS and US occurrences were thus rendered discontiguous, which was expected to impede conditioning compared with contiguous CS-US pairing. Conditioned freezing to the CS was measured in a retention test conducted 48 h after conditioning. The genetic disruption significantly modified the temporal dynamics of the freezing response over the course of the 8-min presentation of the CS, although the immediate conditioned response to the CS was unaffected. The separation between "trace" and "no-trace" conditions was augmented in the mutant mice, but this only became apparent in mid-session; and the augmentation can be attributed to the combined effects of (i) weaker conditioned freezing in the mutant relative to control subjects in the "trace" condition, and (ii) stronger conditioned freezing in mutants relative controls in the "no-trace" condition. The demonstrated increased sensitivity to the effect of CS-US temporal discontiguity further highlights the importance of GlyT1-dependent mechanisms in the regulation of associative learning.

Efficacy and safety of transcranial pulse stimulation in young adolescents with attention-deficit/hyperactivity disorder: a pilot, randomized, double-blind, sham-controlled trial.

Background: This is the first study to evaluate the efficacy and safety of transcranial pulse stimulation (TPS) for the treatment of attention-deficit/hyperactivity disorder (ADHD) among young adolescents in Hong Kong. Methods: This double-blind, randomized, sham-controlled trial included a TPS group and a sham TPS group, encompassing a total of 30 subjects aged 12-17 years who were diagnosed with ADHD. Baseline measurements SNAP-IV, ADHD RS-IV, CGI and executive functions (Stroop tests, Digit Span) and post-TPS evaluation were collected. Both groups were assessed at baseline, immediately after intervention, and at 1-month and 3-month follow-ups. Repeated-measures ANOVAs were used to analyze data. Results: The TPS group exhibited a 30% reduction in the mean SNAP-IV score at postintervention that was maintained at 1- and 3-month follow-ups. Conclusion: TPS is an effective and safe adjunct treatment for the clinical management of ADHD. Clinical trial registration: ClinicalTrials.Gov, identifier NCT05422274.

Partial loss in septo-hippocampal cholinergic neurons alters memory-dependent measures of brain connectivity without overt memory deficits.

The functional relevance of septo-hippocampal cholinergic (SHC) degeneration to the degradation of hippocampus-dependent declarative memory (DM) in aging and Alzheimer's disease (AD) remains ill-defined. Specifically, selective SHC lesions often fail to induce overt memory impairments in animal models. In spite of apparent normal performance, however, neuronal activity within relevant brain structures might be altered by SHC disruption. We hypothesized that partial SHC degeneration may contribute to functional alterations within memory circuits occurring in aging before DM decline. In young adult mice, we studied the effects of behaviorally ineffective (saporin-induced) SHC lesions - similar in extent to that seen in aged animals - on activity patterns and functional connectivity between three main neural memory systems: the septo-hippocampal system, the striatum and the amygdala that sustain declarative, procedural and emotional memory, respectively. Animals were trained in a radial maze procedure dissociating the human equivalents of relational/DM and non-R/DM expressions in animals. Test-induced Fos activation pattern revealed that the partial SHC lesion significantly altered the brain's functional activities and connectivity (co-activation pattern) despite the absence of overt behavioral deficit. Specifically, hippocampal CA3 hyperactivity and abnormal septo-hippocampo-amygdalar inter-connectivity resemble those observed in aging and prodromal AD. Hence, SHC neurons critically coordinate hippocampal function in concert with extra-hippocampal structures in accordance with specific mnemonic demand. Although partial SHC degeneration is not sufficient to impact DM performance by itself, the connectivity change might predispose the emergence of subsequent DM loss when, due to additional age-related insults, the brain can no longer compensate the holistic imbalance caused by cholinergic loss.

A conceptual and practical guide to the behavioural evaluation of animal models of the symptomatology and therapy of schizophrenia.

Schizophrenia is a chronic debilitating brain disorder characterized by a complex set of perceptual and behavioural symptoms that severely disrupt and undermine the patient's psychological well-being and quality of life. Since the exact disease mechanisms remain essentially unknown, holistic animal models are indispensable tools for any serious investigation into the neurobiology of schizophrenia, including the search for remedies, prevention of the disease and possible biological markers. This review provides some practical advice to those confronted with the task of evaluating their animal models for relevance to schizophrenia, a task that inevitably involves behavioural tests with animals. To a novice, this challenge not only is a technical one but also entails attention to interpretative issues concerning validity and translational power. Here, we attempt to offer some guidance to help overcome these obstacles by drawing on our experience of diverse animal models of schizophrenia based on genetics, strain difference, brain lesions, pharmacological induction and early life developmental manipulations. The review pays equal emphasis to the general (theoretical) considerations of experimental design and the illustration of the problems related to critical test parameters and the data analysis of selected exemplar behavioural tests. Finally, the individual differences of behavioural expression in relevant tests observed in wild-type animals might offer an alternative approach in order to explore the mechanism of schizophrenia-related behavioural dysfunction at the molecular, cellular and structural levels, all of which are of more immediate relevance to cell and tissue research.

Molecular and behavioral changes associated with adult hippocampus-specific SynGAP1 knockout.

The synaptic Ras/Rap-GTPase-activating protein (SynGAP1) plays a unique role in regulating specific downstream intracellular events in response to N-methyl-D-aspartate receptor (NMDAR) activation. Constitutive heterozygous loss of SynGAP1 disrupts NMDAR-mediated physiological and behavioral processes, but the disruptions might be of developmental origin. Therefore, the precise role of SynGAP1 in the adult brain, including its relative functional significance within specific brain regions, remains unexplored. The present study constitutes the first attempt in achieving adult hippocampal-specific SynGAP1 knockout using the Cre/loxP approach. Here, we report that this manipulation led to a significant numerical increase in both small and large GluA1 and NR1 immunoreactive clusters, many of which were non-opposed to presynaptic terminals. In parallel, the observed marked decline in the amplitude of spontaneous excitatory currents (sEPSCs) and inter-event intervals supported the impression that SynGAP1 loss might facilitate the accumulation of extrasynaptic glutamatergic receptors. In addition, SynGAP1-mediated signaling appears to be critical for the proper integration and survival of newborn neurons. The manipulation impaired reversal learning in the probe test of the water maze and induced a delay-dependent impairment in spatial recognition memory. It did not significantly affect anxiety or reference memory acquisition but induced a substantial elevation in spontaneous locomotor activity in the open field test. Thus, the present study demonstrates the functional significance of SynGAP1 signaling in the adult brain by capturing several changes that are dependent on NMDAR and hippocampal integrity.

The adenosine hypothesis of schizophrenia into its third decade: From neurochemical imbalance to early life etiological risks.

The adenosine hypothesis of schizophrenia was conceptualized about two decades ago in an attempt to integrate two prominent theories of neurochemical imbalance that attribute the pathogenesis of schizophrenia to hyperfunction of the mesocorticolimbic dopamine neurotransmission and hypofunction of cortical glutamate neurotransmission. Given its unique position as an endogenous modulator of both dopamine and glutamate signaling in the brain, adenosine was postulated as a potential new drug target to achieve multiple antipsychotic actions. This new strategy may offer hope for improving treatment, especially in alleviating negative symptoms and cognitive deficits of schizophrenia that do not respond to current medications. To date, however, the adenosine hypothesis has yet led to any significant therapeutic breakthroughs. Here, we address two possible reasons for the impasse. First, neither the presence of adenosine functional deficiency in people with schizophrenia nor its causal relationship to symptom production has been satisfactorily examined. Second, the lack of novel adenosine-based drugs also impedes progress. This review updates the latest preclinical and clinical data pertinent to the construct validity of the adenosine hypothesis and explores novel molecular processes whereby dysregulation of adenosine signaling could be linked to the etiology of schizophrenia. It is intended to stimulate and revitalize research into the adenosine hypothesis towards the development of a new and improved generation of antipsychotic drugs that has eluded us for decades.

Coexpression of anticipatory and consummatory volitional deficits in schizophrenia and their association with memory impairment.

Avolition in schizophrenia has been attributed to the decoupling between emotion and motivation rather than an inability to perceive or distinguish emotions. Hence, goal-directed behavior incentivized by positive or negative reinforcement becomes impoverished and dull. It is further suggested that goal-directed actions directed at future outcomes (anticipatory or representational response) are preferentially affected, as opposed to actions directed to the current state of affairs (consummatory or evoked response). Attempts to dissociate them behaviorally using the "anticipatory and consummatory pleasure" (ACP) task have demonstrated deficits in both components, yet some have claimed otherwise. In this replication study, we presented further characterization of the pronounced deficits in valence-dependent consummatory as well as anticipatory responding in 40 subjects with schizophrenia in comparison with 42 healthy subjects. In addition, two novel observations were made. First, the correlation between ratings of emotional intensity and arousal levels of pictures used to motivate responding in the ACP task was markedly attenuated in the schizophrenic (SZ) group, suggesting that the decoupling from emotion may be manifested beyond goal-directed behavior in schizophrenia. Second, multiple correlations between ACP performance indices and individual scores in the letter-number span test were uniquely observed in the SZ group, not among healthy controls. The co-emergence of ACP and working memory deficiency in SZ may be linked to common psychopathological processes. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Evaluating the efficacy and safety of transcranial pulse stimulation on adolescents with attention deficit hyperactivity disorder: Study protocol of a pilot randomized, double-blind, sham-controlled trial.

Background: Traditional treatment alone might not effectively control the severity of attention deficit hyperactivity disorder (ADHD) symptoms. Transcranial pulse stimulation (TPS) is a non-invasive brain stimulation (NIBS) technology used on older adults with mild neurocognitive disorders and adults with major depressive disorder. However, there has been no study conducted on young adolescents with ADHD. This will be the first nationwide study evaluating the efficacy and safety of TPS in the treatment of ADHD among young adolescents in Hong Kong. Methods: This study proposes a double-blinded, randomized, sham-controlled trial including TPS as an intervention group and a sham TPS group. Both groups will be measured at baseline (T1), immediately after the intervention (T2), and at the 1-month (T3) and 3-month follow-ups (T4). Recruitment: A total of 30 subjects aged between 12 and 17 years, diagnosed with attention deficit hyperactivity disorder (ADHD), will be recruited in this study. All subjects will be computer randomized into either the intervention group or the sham TPS group on a 1:1 ratio. Intervention: All subjects in each group will have to undertake functional MRI (fMRI) before and after six 30-min TPS sessions, which will be completed in 2 weeks' time. Outcomes: Baseline measurements and post-TPS evaluation of the ADHD symptoms and executive functions will also be conducted on all participants. The 1- and 3-month follow-up periods will be used to assess the long-term sustainability of the TPS intervention. For statistical analysis, ANOVA with repeated measures will be used to analyze data. Missing data were managed by multiple imputations. The level of significance will be set to p < 0.05. Significance of the study: Results emerging from this study will generate new knowledge to ascertain whether TPS can be used as a top-on treatment for ADHD. Clinical trial registration: clinicaltrails.gov, identifier: NCT05422274.

In male rats with concurrent iron and (n-3) fatty acid deficiency, provision of either iron or (n-3) fatty acids alone alters monoamine metabolism and exacerbates the cognitive deficits associated with combined deficiency.

Concurrent deficiencies of iron (Fe) (ID) and (n-3) fatty acids [(n-3)FAD)] in rats can alter brain monoamine pathways and impair learning and memory. We examined whether repletion with Fe and DHA/EPA, alone and in combination, corrects the deficits in brain monoamine activity (by measuring monoamines and related gene expression) and spatial working and reference memory [by Morris water maze (MWM) testing] associated with deficiency. Using a 2 × 2 design, male rats with concurrent ID and (n-3)FAD [ID+(n-3)FAD] were fed an Fe+DHA/EPA, Fe+(n-3)FAD, ID+DHA/EPA, or ID+(n-3)FAD diet for 5 wk [postnatal d 56-91]. Biochemical measures and MWM performance after repletion were compared to age-matched control rats. The provision of Fe in combination with DHA/EPA synergistically increased Fe concentrations in the olfactory bulb (OB) (Fe x DHA/EPA interaction). Similarly, provision of DHA/EPA in combination with Fe resulted in higher brain DHA concentrations than provision of DHA alone in the frontal cortex (FC) and OB (P < 0.05). Dopamine (DA) receptor D1 was upregulated in the hippocampus of Fe+DHA/EPA rats (fold-change = 1.25; P < 0.05) and there were significant Fe x DHA/EPA interactions on serotonin (5-HT) in the OB and on the DA metabolite dihydroxyphenylacetic acid in the FC and striatum. Working memory performance was impaired in ID+DHA/EPA rats compared with controls (P < 0.05). In the reference memory task, Fe+DHA/EPA improved learning behavior, but Fe or DHA/EPA alone did not. These findings suggest that feeding either Fe or DHA/EPA alone to adult rats with both ID and (n-3)FAD affects the DA and 5-HT pathways differently than combined repletion and exacerbates the cognitive deficits associated with combined deficiency.

Combined deficiency of iron and (n-3) fatty acids in male rats disrupts brain monoamine metabolism and produces greater memory deficits than iron deficiency or (n-3) fatty acid deficiency alone.

Deficiencies of iron (Fe) (ID) and (n-3) fatty acids (FA) [(n-3)FAD] may impair brain development and function through shared mechanisms. However, little is known about the potential interactions between these 2 common deficiencies. We studied the effects of ID and (n-3)FAD, alone and in combination, on brain monoamine pathways (by measuring monoamines and related gene expression) and spatial working and reference memory (by Morris water maze testing). Using a 2 × 2 design, male rats were fed an ID, (n-3)FAD, ID+(n-3)FAD, or control diet for 5 wk postweaning (postnatal d 21-56) after (n-3)FAD had been induced over 2 generations. The (n-3)FAD and ID diets decreased brain (n-3) FA by 70-76% and Fe by 20-32%, respectively. ID and (n-3)FAD significantly increased dopamine (DA) concentrations in the olfactory bulb (OB) and striatum, with an additive 1- to 2-fold increase in ID+(n-3)FAD rats compared with controls (P < 0.05). ID decreased serotonin (5-HT) levels in OB, with a significant decrease in ID+(n-3)FAD rats. Furthermore, norepinephrine concentrations were increased 2-fold in the frontal cortex (FC) of (n-3)FAD rats (P < 0.05). Dopa decarboxylase was downregulated in the hippocampus of ID and ID+(n-3)FAD rats (fold-change = -1.33; P < 0.05). ID and (n-3)FAD significantly impaired working memory performance and the impairment positively correlated with DA concentrations in FC (r = 0.39; P = 0.026). Reference memory was impaired in the ID+(n-3)FAD rats (P < 0.05) and was negatively associated with 5-HT in FC (r = -0.42; P = 0.018). These results suggest that the combined deficiencies of Fe and (n-3) FA disrupt brain monoamine metabolism and produce greater deficits in reference memory than ID or (n-3)FAD alone.

Selective inactivation of adenosine A(2A) receptors in striatal neurons enhances working memory and reversal learning.

The adenosine A(2A) receptor (A(2A)R) is highly enriched in the striatum where it is uniquely positioned to integrate dopaminergic, glutamatergic, and other signals to modulate cognition. Although previous studies support the hypothesis that A(2A)R inactivation can be pro-cognitive, analyses of A(2A)R's effects on cognitive functions have been restricted to a small subset of cognitive domains. Furthermore, the relative contribution of A(2A)Rs in distinct brain regions remains largely unknown. Here, we studied the regulation of multiple memory processes by brain region-specific populations of A(2A)Rs. Specifically, we evaluated the cognitive impacts of conditional A(2A)R deletion restricted to either the entire forebrain (i.e., cerebral cortex, hippocampus, and striatum, fb-A(2A)R KO) or to striatum alone (st-A(2A)R KO) in recognition memory, working memory, reference memory, and reversal learning. This comprehensive, comparative analysis showed for the first time that depletion of A(2A)R-dependent signaling in either the entire forebrain or striatum alone is associated with two specific phenotypes indicative of cognitive flexibility-enhanced working memory and enhanced reversal learning. These selective pro-cognitive phenotypes seemed largely attributed to inactivation of striatal A(2A)Rs as they were captured by A(2A)R deletion restricted to striatal neurons. Neither spatial reference memory acquisition nor spatial recognition memory were grossly affected, and no evidence for compensatory changes in striatal or cortical D(1), D(2), or A(1) receptor expression was found. This study provides the first direct demonstration that targeting striatal A(2A)Rs may be an effective, novel strategy to facilitate cognitive flexibility under normal and pathologic conditions.

Monoallelic loss of the F-actin-binding protein radixin facilitates startle reactivity and pre-pulse inhibition in mice.

Hearing impairment is one of the most common disorders with a global burden and increasing prevalence in an ever-aging population. Previous research has largely focused on peripheral sensory perception, while the brain circuits of auditory processing and integration remain poorly understood. Mutations in the rdx gene, encoding the F-actin binding protein radixin (Rdx), can induce hearing loss in human patients and homozygous depletion of Rdx causes deafness in mice. However, the precise physiological function of Rdx in hearing and auditory information processing is still ill-defined. Here, we investigated consequences of rdx monoallelic loss in the mouse. Unlike the homozygous (-/-) rdx knockout, which is characterized by the degeneration of actin-based stereocilia and subsequent hearing loss, our analysis of heterozygous (+/-) mutants has revealed a different phenotype. Specifically, monoallelic loss of rdx potentiated the startle reflex in response to acoustic stimulation of increasing intensities, suggesting a gain of function relative to wildtype littermates. The monoallelic loss of the rdx gene also facilitated pre-pulse inhibition of the acoustic startle reflex induced by weak auditory pre-pulse stimuli, indicating a modification to the circuit underlying sensorimotor gating of auditory input. However, the auditory brainstem response (ABR)-based hearing thresholds revealed a mild impairment in peripheral sound perception in rdx (+/-) mice, suggesting minor aberration of stereocilia structural integrity. Taken together, our data suggest a critical role of Rdx in the top-down processing and/or integration of auditory signals, and therefore a novel perspective to uncover further Rdx-mediated mechanisms in central auditory information processing.

Within-subjects vs between-subjects co-variation of prepulse-elicited reaction and the diminution of startle to the succeeding pulse stimulus in the prepulse inhibition paradigm.

Prepulse inhibition (PPI) refers to the diminution of the startle reflex to a sudden and intense acoustic stimulus (pulse) when this startle-eliciting pulse is preceded shortly by a weaker prepulse stimulus. PPI is widely used in evaluating the effects of psychomimetic and antipsychotic drugs on sensorimotor gating, but individual differences in PPI expression have received scant attention. We have previously shown that mice and rats exhibiting stronger motor response to the prepulse also exhibit more PPI. It remains unexplored, however, if this between-subjects correlation may be similarly observed across trials from a within-subjects perspective. Here, we mapped the prepulse-elicited response to the diminution of the startle response to the succeeding pulse stimulus, trial-by-trial, across nine prepulse-pulse definitions with varying prepulse and pulse intensities. The resulting within-subjects correlation independently obtained in 113 adult C57BL6 mice revealed that trials registering a stronger prepulse reaction also recorded a larger startle response to the pulse stimulus, indicative of weaker PPI, especially when higher-intensity prepulses were paired with low-intensity pulses. The within- and between-subjects analyses have apparently yielded two contrasting relationships between the direct motor response to the prepulse and the inhibition of subsequent startle reaction induced by the same prepulse. One interpretation is that the within-subjects correlation reflects state-dependent variation, whereas the between-subjects correlation stems from trait-dependent individual variation. Finally, whether our present findings may depend on the nature of the prepulse reaction is further discussed.

Constitutive genetic deletion of the growth regulator Nogo-A induces schizophrenia-related endophenotypes.

The membrane protein Nogo-A, which is predominantly expressed by oligodendrocytes in the adult CNS and by neurons mainly during development, is well known for limiting neurite outgrowth and regeneration in the injured mammalian CNS. In addition, it has recently been proposed that abnormal Nogo-A expression or Nogo receptor (NgR) mutations may confer genetic risks for neuropsychiatric disorders of presumed neurodevelopmental origin, such as schizophrenia. We therefore evaluated whether Nogo-A deletion may lead to schizophrenia-like abnormalities in a mouse model of genetic Nogo-A deficiency. Here, we show that systemic, lifelong knock-out of the Nogo-A gene can lead to specific behavioral abnormalities resembling schizophrenia-related endophenotypes: deficient sensorimotor gating, disrupted latent inhibition, perseverative behavior, and increased sensitivity to the locomotor stimulating effects of amphetamine. These behavioral phenotypes were accompanied by altered monoaminergic transmitter levels in specific striatal and limbic structures, as well as changes in dopamine D2 receptor expression in the same brain regions. Nogo-A deletion was further associated with elevated expression of growth-related markers. In contrast, acute antibody-mediated Nogo-A neutralization in adult wild-type mice failed to produce such phenotypes, suggesting that the phenotypes observed in the knock-out mice might be of developmental origin, and that Nogo-A normally subserves critical functions in neurodevelopment. This study provides the first experimental demonstration that Nogo-A bears neuropsychiatric relevance, and alterations in its expression may be one etiological factor in schizophrenia and related disorders.

Examining the sex- and circadian dependency of a learning phenotype in mice with glycine transporter 1 deletion in two Pavlovian conditioning paradigms.

Behavioural characterisation of transgenic mice has been instrumental in search of therapeutic targets for the modulation of cognitive function. However, little effort has been devoted to phenotypic characterisation across environmental conditions and genomic differences such as sex and strain, which is essential to translational research. The present study is an effort in this direction. It scrutinised the stability and robustness of the phenotype of enhanced Pavlovian conditioning reported in mice with forebrain neuronal deletion of glycine transporter 1 by evaluating the possible presence of sex and circadian dependency, and its consistency across aversive and appetitive conditioning paradigms. The Pavlovian phenotype was essentially unaffected by the time of testing between the two circadian phases, but it was modified by sex in both conditioning paradigms. We observed that the effect size of the phenotype was strongest in female mice tested during the dark phase in the aversive paradigm. Critically, the presence of the phenotype in female mutants was accompanied by an increase in resistance to extinction. Similarly, enhanced conditioned responding once again emerged solely in female mutants in the appetitive conditioning experiment, which was again associated with an increased resistance to extinction across days, but male mutants exhibited an opposite trend towards facilitation of extinction. The present study has thus added hitherto unknown qualifications and specifications of a previously reported memory enhancing phenotype in this mouse line by identifying the determinants of the magnitude and direction of the expressed phenotype. This in-depth comparative approach is of value to the interpretation of behavioural findings in general.