Linking Social Cognition, Parvalbumin Interneurons, and Oxytocin in Alzheimer's Disease: An Update.

Finding a cure for Alzheimer's disease (AD) has been notoriously challenging for many decades. Therefore, the current focus is mainly on prevention, timely intervention, and slowing the progression in the earliest stages. A better understanding of underlying mechanisms at the beginning of the disease could aid in early diagnosis and intervention, including alleviating symptoms or slowing down the disease progression. Changes in social cognition and progressive parvalbumin (PV) interneuron dysfunction are among the earliest observable effects of AD. Various AD rodent models mimic these early alterations, but only a narrow field of study has considered their mutual relationship. In this review, we discuss current knowledge about PV interneuron dysfunction in AD and emphasize their importance in social cognition and memory. Next, we propose oxytocin (OT) as a potent modulator of PV interneurons and as a promising treatment for managing some of the early symptoms. We further discuss the supporting evidence on its beneficial effects on AD-related pathology. Clinical trials have employed the use of OT in various neuropsychiatric diseases with promising results, but little is known about its prospective impacts on AD. On the other hand, the modulatory effects of OT in specific structures and local circuits need to be clarified in future studies. This review highlights the connection between PV interneurons and social cognition impairment in the early stages of AD and considers OT as a promising therapeutic agent for addressing these early deficits.

Dopaminergic and glutamatergic models of psychosis show differential sensitivity to aripiprazole and a novel experimental compound modulating D2/5-HT receptor activity.

Dopamine type 2 receptors (D2Rs) constitute the main molecular target in the pharmacotherapy of schizophrenia. However, the second and third generation of antipsychotics comprises multi-target ligands, also binding serotonin type 3 receptors (5-HT3Rs) and other receptor classes as well. Here, we examined two experimental compounds (marked compound K1697 and K1700) from the group of 1,4-di-substituted aromatic piperazines, previously described in the study of Juza et al., 2021, and compared them with the chosen reference antipsychotic, aripiprazole. Their efficacy against schizophrenia-like behavior was tested in two different models of psychosis in the rat, induced by acute administration of either amphetamine (1.5 mg/kg) or dizocilpine (0.1 mg/kg), reflecting the dopaminergic and glutamatergic hypotheses of schizophrenia. The two models exhibited broadly similar behavioral manifestations: hyperlocomotion, disrupted social behavior and impaired prepulse inhibition of the startle response. However, they differed in their treatment responses as hyperlocomotion and prepulse inhibition deficit in the dizocilpine model were resistant to antipsychotic treatment, unlike the amphetamine model. One of the experimental compounds, K1700, ameliorated all the observed schizophrenia-like behaviors in the amphetamine model with an efficacy comparable to or greater than aripiprazole. Whereas social impairments caused by dizocilpine were strongly suppressed by aripiprazole, K1700 was less efficient. Taken together, K1700 showed antipsychotic properties comparable to those of aripiprazole, although the efficacy of the two drugs differed in specific domains of behavior and was also model-dependent. Our present results highlight the differences in these two schizophrenia models and their responsiveness to pharmacotherapy, and confirm compound K1700 as a promising drug candidate.

Incidental temporal binding in rats: A novel behavioral task.

We designed a behavioral task called One-Trial Trace Escape Reaction (OTTER), in which rats incidentally associate two temporally discontinuous stimuli: a neutral acoustic cue (CS) with an aversive stimulus (US) which occurs two seconds later (CS-2s-US sequence). Rats are first habituated to two similar environmental contexts (A and B), each consisting of an interconnected dark and light chamber. Next, rats experience the CS-2s-US sequence in the dark chamber of one of the contexts (either A or B); the US is terminated immediately after a rat escapes into the light chamber. The CS-2s-US sequence is presented only once to ensure the incidental acquisition of the association. The recall is tested 24 h later when rats are presented with only the CS in the alternate context (B or A), and their behavioral response is observed. Our results show that 59% of the rats responded to the CS by escaping to the light chamber, although they experienced only one CS-2s-US pairing. The OTTER task offers a flexible high throughput tool to study memory acquired incidentally after a single experience. Incidental one-trial acquisition of association between temporally discontinuous events may be one of the essential components of episodic memory formation.

The role of optogenetic stimulations of parvalbumin-positive interneurons in the prefrontal cortex and the ventral hippocampus on an acute MK-801 model of schizophrenia-like cognitive inflexibility.

Schizophrenia research has increased in recent decades and focused more on its neural basis. Decision-making and cognitive flexibility are the main cognitive functions that are impaired and considered schizophrenia endophenotypes. Cognitive impairment was recently connected with altered functions of N-methyl-d-aspartate (NMDAR) glutamatergic receptors, which increased cortical activity. Selective NMDAR antagonists, such as MK-801, have been used to model cognitive inflexibility in schizophrenia. Decreased GABAergic inhibitory activity has been shown elsewhere with enhanced cortical activity. This imbalance in the excitatory/inhibitory may reduce the entrainment of prefrontal gamma and hippocampal theta rhythms and result in gamma/theta band de-synchronization. The current study established an acute MK-801 administration model of schizophrenia-like cognitive inflexibility in rats and used the attentional set-shifting task in which rats learned to switch/reverse the relevant rule. During the task, we used in vivo optogenetic stimulations of parvalbumin-positive interneurons at specific light pulses in the prefrontal cortex and ventral hippocampus. The first experiments showed that acute dizocilpine in rats produced schizophrenia-like cognitive inflexibility. The second set of experiments demonstrated that specific optogenetic stimulation at specific frequencies of parvalbumin-positive interneurons in the prefrontal cortex and ventral hippocampus rescued the cognitive flexibility rats that received acute MK-801. These findings advance our knowledge of the pivotal role of parvalbumin interneurons in schizophrenia-like cognitive impairment and may guide further research on this severe psychiatric disorder.

Infectious origin of Alzheimer's disease: Amyloid beta as a component of brain antimicrobial immunity.

The amyloid cascade hypothesis, focusing on pathological proteins aggregation, has so far failed to uncover the root cause of Alzheimer's disease (AD), or to provide an effective therapy. This traditional paradigm essentially explains a mechanism involved in the development of sporadic AD rather than its cause. The failure of an overwhelming majority of clinical studies (99.6%) demonstrates that a breakthrough in therapy would be difficult if not impossible without understanding the etiology of AD. It becomes more and more apparent that the AD pathology might originate from brain infection. In this review, we discuss a potential role of bacteria, viruses, fungi, and eukaryotic parasites as triggers of AD pathology. We show evidence from the current literature that amyloid beta, traditionally viewed as pathological, actually acts as an antimicrobial peptide, protecting the brain against pathogens. However, in case of a prolonged or excessive activation of a senescent immune system, amyloid beta accumulation and aggregation becomes damaging and supports runaway neurodegenerative processes in AD. This is paralleled by the recent study by Alam and colleagues (2022) who showed that alpha-synuclein, the protein accumulating in synucleinopathies, also plays a critical physiological role in immune reactions and inflammation, showing an unforeseen link between the 2 unrelated classes of neurodegenerative disorders. The multiplication of the amyloid precursor protein gene, recently described by Lee and collegues (2018), and possible reactivation of human endogenous retroviruses by pathogens fits well into the same picture. We discuss these new findings from the viewpoint of the infection hypothesis of AD and offer suggestions for future research.

Systems genetics in the rat HXB/BXH family identifies Tti2 as a pleiotropic quantitative trait gene for adult hippocampal neurogenesis and serum glucose.

Neurogenesis in the adult hippocampus contributes to learning and memory in the healthy brain but is dysregulated in metabolic and neurodegenerative diseases. The molecular relationships between neural stem cell activity, adult neurogenesis, and global metabolism are largely unknown. Here we applied unbiased systems genetics methods to quantify genetic covariation among adult neurogenesis and metabolic phenotypes in peripheral tissues of a genetically diverse family of rat strains, derived from a cross between the spontaneously hypertensive (SHR/OlaIpcv) strain and Brown Norway (BN-Lx/Cub). The HXB/BXH family is a very well established model to dissect genetic variants that modulate metabolic and cardiovascular diseases and we have accumulated deep phenome and transcriptome data in a FAIR-compliant resource for systematic and integrative analyses. Here we measured rates of precursor cell proliferation, survival of new neurons, and gene expression in the hippocampus of the entire HXB/BXH family, including both parents. These data were combined with published metabolic phenotypes to detect a neurometabolic quantitative trait locus (QTL) for serum glucose and neuronal survival on Chromosome 16: 62.1-66.3 Mb. We subsequently fine-mapped the key phenotype to a locus that includes the Telo2-interacting protein 2 gene (Tti2)-a chaperone that modulates the activity and stability of PIKK kinases. To verify the hypothesis that differences in neurogenesis and glucose levels are caused by a polymorphism in Tti2, we generated a targeted frameshift mutation on the SHR/OlaIpcv background. Heterozygous SHR-Tti2+/- mutants had lower rates of hippocampal neurogenesis and hallmarks of dysglycemia compared to wild-type littermates. Our findings highlight Tti2 as a causal genetic link between glucose metabolism and structural brain plasticity. In humans, more than 800 genomic variants are linked to TTI2 expression, seven of which have associations to protein and blood stem cell factor concentrations, blood pressure and frontotemporal dementia.

Selective impairment of timing in a NMDA hypofunction animal model of psychosis.

Schizophrenia is severe neuropsychiatric disease, which is commonly accompanied not only by positive or negative symptoms, but also by cognitive impairment. To study neuronal mechanisms underlying cognitive distortions and mechanisms underlying schizophrenia, animal pharmacological models of cognitive symptoms are commonly used. Between various cognitive impairments in schizophrenia patients, disturbed time perception has often been reported. Here, we examined temporal and spatial cognition in a modified Carousel maze task in the animal model of schizophrenia induced by non-competitive NMDA-receptor antagonists MK-801. Male Long-Evans rats (n = 18) first learned to avoid the aversive sector on a rotating arena in both dark and light intervals. We verified that during dark, rats used temporal cues, while during light they relied predominantly on spatial cues. We demonstrated that the timing strategy depends on the stable rotation speed of the arena and on the repositioning clues such as aversive stimuli. During testing (both in light and dark intervals), half of the rats received MK-801 and the control half received saline solution. We observed dose-dependent disruptions of both temporal and spatial cognition. Namely, both doses of MK-801 (0.1 and 0.12 mg/kg) significantly impaired timing strategy in the dark and increased locomotor activity. MK-801 dose 0.1 mg/kg, but not 0.12, also impaired spatial avoidance strategy in light. We found that the timing strategy is more sensitive to NMDA antagonist MK-801 than the spatial strategy. To conclude, a modified version of the Carousel maze is a useful and sensitive tool for detecting timing impairments in the MK-801 induced rodent model of schizophrenia.

Selective deficits in attentional set-shifting in mice induced by maternal immune activation with poly(I:C).

Maternal immune activation has been identified as a significant risk factor for schizophrenia. Using rodent models, past work has demonstrated various behavioral and brain impairments in offspring after immune-activating events. We applied 5 mg/kg of poly(I:C) on gestation day 9 to pregnant mouse dams, whose offspring were then stressed during puberty. We show impairments in attentional set-shifting in a T-maze, and a decreased number of parvalbumin-positive interneurons in the hippocampus as a result of peripubertal stress specifically in females.

Memantine and Riluzole Exacerbate, Rather Than Ameliorate Behavioral Deficits Induced by 8-OH-DPAT Sensitization in a Spatial Task.

Chronic sensitization to serotonin 1A and 7 receptors agonist 8-OH-DPAT induces compulsive checking and perseverative behavior. As such, it has been used to model obsessive-compulsive disorder (OCD)-like behavior in mice and rats. In this study, we tested spatial learning in the 8-OH-DPAT model of OCD and the effect of co-administration of memantine and riluzole-glutamate-modulating agents that have been shown to be effective in several clinical trials. Rats were tested in the active place avoidance task in the Carousel maze, where they learned to avoid the visually imperceptible shock sector. All rats were subcutaneously injected with 8-OH-DPAT (0.25 mg/kg) or saline (control group) during habituation. During acquisition, they were pretreated with riluzole (1 mg/kg), memantine (1 mg/kg), or saline solution 30 min before each session and injected with 8-OH-DPAT ("OH" groups) or saline ("saline" groups) right before the experiment. We found that repeated application of 8-OH-DPAT during both habituation and acquisition significantly increased locomotion, but it impaired the ability to avoid the shock sector. However, the application of 8-OH-DPAT in habituation had no impact on the learning process if discontinued in acquisition. Similarly, memantine and riluzole did not affect the measured parameters in the "saline" groups, but in the "OH" groups, they significantly increased locomotion. In addition, riluzole increased the number of entrances and decreased the maximum time avoided of the shock sector. We conclude that monotherapy with glutamate-modulating agents does not reduce but exacerbates cognitive symptoms in the animal model of OCD.

Roles of the ventral hippocampus and medial prefrontal cortex in spatial reversal learning and attentional set-shifting.

Neural components enabling flexible cognition and behavior are well-established, and depend mostly on proper intercommunication within the prefrontal cortex (PFC) and striatum. However, dense projections from the ventral hippocampus (vHPC) alter the functioning of the medial PFC (mPFC). Dysfunctional hippocampo-prefrontal connectivity negatively affects the integrity of flexible cognition, especially in patients with schizophrenia. In this study, we aimed to test the role of the vHPC and mPFC in a place avoidance task on a rotating arena using two spatial flexibility task variants - reversal learning and set-shifting. To achieve this, we inactivated each of these structures in adult male Long-Evans rats by performing bilateral local muscimol (a GABAA receptor agonist) injections. A significantly disrupted performance was observed in reversal learning in the vHPC-inactivated, but not in the mPFC-inactivated rats. These results confirm the notion that the vHPC participates in some forms of behavioral flexibility, especially when spatial cues are needed. It seems, rather unexpectedly, that the mPFC is not taxed in these flexibility tasks on a rotating arena.

Schizophrenia, the gut microbiota, and new opportunities from optogenetic manipulations of the gut-brain axis.

Schizophrenia research arose in the twentieth century and is currently rapidly developing, focusing on many parallel research pathways and evaluating various concepts of disease etiology. Today, we have relatively good knowledge about the generation of positive and negative symptoms in patients with schizophrenia. However, the neural basis and pathophysiology of schizophrenia, especially cognitive symptoms, are still poorly understood. Finding new methods to uncover the physiological basis of the mental inabilities related to schizophrenia is an urgent task for modern neuroscience because of the lack of specific therapies for cognitive deficits in the disease. Researchers have begun investigating functional crosstalk between NMDARs and GABAergic neurons associated with schizophrenia at different resolutions. In another direction, the gut microbiota is getting increasing interest from neuroscientists. Recent findings have highlighted the role of a gut-brain axis, with the gut microbiota playing a crucial role in several psychopathologies, including schizophrenia and autism.There have also been investigations into potential therapies aimed at normalizing altered microbiota signaling to the enteric nervous system (ENS) and the central nervous system (CNS). Probiotics diets and fecal microbiota transplantation (FMT) are currently the most common therapies. Interestingly, in rodent models of binge feeding, optogenetic applications have been shown to affect gut colony sensitivity, thus increasing colonic transit. Here, we review recent findings on the gut microbiota-schizophrenia relationship using in vivo optogenetics. Moreover, we evaluate if manipulating actors in either the brain or the gut might improve potential treatment research. Such research and techniques will increase our knowledge of how the gut microbiota can manipulate GABA production, and therefore accompany changes in CNS GABAergic activity.

Transient Inactivation of the Medial Prefrontal Cortex and Ventral Hippocampus Impairs Active Place Avoidance Retrieval on a Rotating Arena.

It is well known that communication between the medial prefrontal cortex (mPFC) and the ventral hippocampus (vHPC) is critical for various cognitive and behavioral functions. However, the exact role of these structures in spatial coordination remains to be clarified. Here we sought to determine the involvement of the mPFC and the vHPC in the spatial retrieval of a previously learned active place avoidance task in adult male Long-Evans rats, using a combination of unilateral and bilateral local muscimol inactivations. Moreover, we tested the role of the vHPC-mPFC pathway by performing combined ipsilateral and contralateral inactivations. Our results showed not only bilateral inactivations of either structure, but also the combined inactivations impaired the retrieval of spatial memory, whereas unilateral one-structure inactivations did not yield any effect. Remarkably, muscimol injections in combined groups exerted similar deficits, regardless of whether the inactivations were contralateral or ipsilateral. These findings confirm the importance of these structures in spatial cognition and emphasize the importance of the intact functioning of the vHPC-mPFC pathway.

Behavioral Alterations and Decreased Number of Parvalbumin-Positive Interneurons in Wistar Rats after Maternal Immune Activation by Lipopolysaccharide: Sex Matters.

Maternal immune activation (MIA) during pregnancy represents an important environmental factor in the etiology of schizophrenia and autism spectrum disorders (ASD). Our goal was to investigate the impacts of MIA on the brain and behavior of adolescent and adult offspring, as a rat model of these neurodevelopmental disorders. We injected bacterial lipopolysaccharide (LPS, 1 mg/kg) to pregnant Wistar dams from gestational day 7, every other day, up to delivery. Behavior of the offspring was examined in a comprehensive battery of tasks at postnatal days P45 and P90. Several brain parameters were analyzed at P28. The results showed that prenatal immune activation caused social and communication impairments in the adult offspring of both sexes; males were affected already in adolescence. MIA also caused prepulse inhibition deficit in females and increased the startle reaction in males. Anxiety and hypolocomotion were apparent in LPS-affected males and females. In the 28-day-old LPS offspring, we found enlargement of the brain and decreased numbers of parvalbumin-positive interneurons in the frontal cortex in both sexes. To conclude, our data indicate that sex of the offspring plays a crucial role in the development of the MIA-induced behavioral alterations, whereas changes in the brain apparent in young animals are sex-independent.

Plasticity-Related Activity in the Hippocampus, Anterior Cingulate, Orbitofrontal, and Prefrontal Cortex Following a Repeated Treatment with D2/D3 Agonist Quinpirole.

Quinpirole (QNP) sensitization is a well-established model of stereotypical checking relevant to obsessive-compulsive disorder. Previously, we found that QNP-treated rats display deficits in hippocampus-dependent tasks. The present study explores the expression of immediate early genes (IEG) during QNP-induced stereotypical checking in the hippocampus, anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), and medial prefrontal cortex (mPFC). Adult male rats were injected with QNP (0.5 mg/mL/kg; n = 15) or saline (n = 14) daily for 10 days and exposed to an arena enriched with two objects. Visits to the objects and the corners of the arena were recorded. QNP-treated rats developed an idiosyncratic pattern of visits that persisted across experimental days. On day 11, rats were exposed to the arena twice for 5 min and sacrificed. The expression of IEGs Arc and Homer1a was determined using cellular compartment analysis of temporal activity by fluorescence in situ hybridization. IEG-positive nuclei were counted in the CA1 area of the hippocampus, ACC, OFC, and mPFC. We found significantly fewer IEG-positive nuclei in the CA1 in QNP-treated rats compared to controls. The overlap between IEG expressing neurons was comparable between the groups. We did not observe significant differences in IEG expression between QNP treated and control rats in ACC, OFC, and mPFC. In conclusion, treatment of rats with quinpirole decreases plasticity-related activity in the hippocampus during stereotypical checking.

Navigation in a Space With Moving Objects: Rats Can Avoid Specific Locations Defined With Respect to a Moving Robot.

Animals can organize their behavior with respect to other moving animals or objects; when hunting or escaping a predator, when migrating in groups or during various social interactions. In rats, we aimed to characterize spatial behaviors relative to moving objects and to explore the cognitive mechanisms controlling these behaviors. Three groups of animals were trained to avoid a mild foot-shock delivered in one of three positions: either in front, on the left side, or on the right side of a moving robot. We showed the rats can recognize and avoid these specific areas. The avoidance behavior specific for the left or right side of the robot demonstrated animals not only react to "simple" stimuli such as increasing noise level or growing retinal image of an approaching object, but they process their spatial position relative to the object. Using an all-white robot without prominent visual patterns that would distinguish its different sides, we showed that the behavior does not depend on responses to prominent visual patterns, but that the rats can guide their navigation according to geometrical spatial relationship relative to the moving object. Rats' competence for navigation in space defined by a moving object resembles navigation abilities in stationary space. Recording of hippocampal single unit activity during rat's interaction with the robot proved feasibility of the task to uncover neuronal mechanism of this type of navigation.

Interactions of 17ß-Hydroxysteroid Dehydrogenase Type 10 and Cyclophilin D in Alzheimer's Disease.

The nucleus-encoded 17ß-hydroxysteroid dehydrogenase type 10 (17ß-HSD10) regulates cyclophilin D (cypD) in the mitochondrial matrix. CypD regulates opening of mitochondrial permeability transition pores. Both mechanisms may be affected by amyloid ß peptides accumulated in mitochondria in Alzheimer's disease (AD). In order to clarify changes occurring in brain mitochondria, we evaluated interactions of both mitochondrial proteins in vitro (by surface plasmon resonance biosensor) and detected levels of various complexes of 17ß-HSD10 formed in vivo (by sandwich ELISA) in brain mitochondria isolated from the transgenic animal model of AD (homozygous McGill-R-Thy1-APP rats) and in cerebrospinal fluid samples of AD patients. By surface plasmon resonance biosensor, we observed the interaction of 17ß-HSD10 and cypD in a direct real-time manner and determined, for the first time, the kinetic parameters of the interaction (ka 2.0 × 105 M1s-1, kd 5.8 × 104 s-1, and KD 3.5 × 10-10 M). In McGill-R-Thy1-APP rats compared to controls, levels of 17ß-HSD10-cypD complexes were decreased and those of total amyloid ß increased. Moreover, the levels of 17ß-HSD10-cypD complexes were decreased in cerebrospinal fluid of individuals with AD (in mild cognitive impairment as well as dementia stages) or with Frontotemporal lobar degeneration (FTLD) compared to cognitively normal controls (the sensitivity of the complexes to AD dementia was 92.9%, that to FTLD 73.8%, the specificity to AD dementia equaled 91.7% in a comparison with the controls but only 26.2% with FTLD). Our results demonstrate the weakened ability of 17ß-HSD10 to regulate cypD in the mitochondrial matrix probably via direct effects of amyloid ß. Levels of 17ß-HSD10-cypD complexes in cerebrospinal fluid seem to be the very sensitive indicator of mitochondrial dysfunction observed in neurodegeneration but unfortunately not specific to AD pathology. We do not recommend it as the new biomarker of AD.

CRMP2 mediates Sema3F-dependent axon pruning and dendritic spine remodeling.

Regulation of axon guidance and pruning of inappropriate synapses by class 3 semaphorins are key to the development of neural circuits. Collapsin response mediator protein 2 (CRMP2) has been shown to regulate axon guidance by mediating semaphorin 3A (Sema3A) signaling; however, nothing is known about its role in synapse pruning. Here, using newly generated crmp2-/- mice we demonstrate that CRMP2 has a moderate effect on Sema3A-dependent axon guidance in vivo, and its deficiency leads to a mild defect in axon guidance in peripheral nerves and the corpus callosum. Surprisingly, crmp2-/- mice display prominent defects in stereotyped axon pruning in hippocampus and visual cortex and altered dendritic spine remodeling, which is consistent with impaired Sema3F signaling and with models of autism spectrum disorder (ASD). We demonstrate that CRMP2 mediates Sema3F signaling in primary neurons and that crmp2-/- mice display ASD-related social behavior changes in the early postnatal period as well as in adults. Together, we demonstrate that CRMP2 mediates Sema3F-dependent synapse pruning and its dysfunction shares histological and behavioral features of ASD.

Comorbidities of early-onset temporal epilepsy: Cognitive, social, emotional, and morphologic dimensions.

Epilepsy, the most common neurologic disorder in childhood, is associated with a subset of psychiatric dysfunctions, including cognitive deficits, and alterations in emotionality (e.g., anxiety and depression) and social functioning. In the present study, we evaluated an integrative set of behavioral responses, including cognitive/socio-cognitive and emotional dimensions, using a number of behavioral paradigms in the LiCl/pilocarpine model of status epilepticus (SE) in rats. The aims of the study were to examine whether SE affects: 1) non-associative learning (habituation of exploratory behavior); 2) investigatory response to an indifferent stimulus object; 3) sociability/social novelty preference; 4) social recognition or discrimination; and 4) short- and long-term memory in the Morris water maze (MWM). Finally, we investigated the morphology of key brain structures involved in the examined behavioral dysfunctions. SE did not affect habituation to an open-field arena in juvenile (P25), adolescent (P32), or adult (P80) rats. SE rats spent less time in the central part of the arena. SE adolescent rats (P32) displayed a higher number of rearings with a shorter duration. SE rats displayed a markedly attenuated investigatory response to an indifferent stimulus object. SE rats in all age groups demonstrated pronounced deficits in sociability and the preference for social novelty. In addition, SE rats spent a reduced amount of time investigating a juvenile rat upon first exposure. After 30 min re-exposure together with an additional, novel juvenile, the SE rats spent equal time investigating both juveniles. In the MWM task, acquisition was unimpaired but there was a deficit in delayed memory retention after 10 days. SE did not affect cognitive flexibility expressed by reversal learning. Together, these findings suggest that early-life SE leads to alterations in emotional/anxiety-related behavior and affects sociability/preference for social novelty and social discrimination. Early-life SE did not alter acquisition of spatial learning, but it impaired delayed retention. Using Fluoro Jade B staining performed 24 h after SE revealed apparent neurodegeneration in the dorsal hippocampus, mediodorsal thalamic nucleus and medial amygdala, brain areas that are critically involved in network underlying emotional behavior and cognitive functions.

A therapeutic dose of memantine improves the performance of rats in an active place avoidance task under the continuous dissociation of distal room and proximal arena cues.

Memory is related to the function of N-methyl-D-aspartate (NMDA) receptors. Depending on the dose, NMDA receptor antagonists (such as memantine or MK-801) can impair memory and/or cognitive as well as procedural functions, while they also can prevent the long-term toxic effects of over-excitation of these receptors in pathophysiological processes. There is an unresolved question of whether memantine at low doses could exert an acute pro-cognitive activity. A therapeutic dose of memantine was found to improve short-term spatial memory tested in the alternation version of active place avoidance in a Carousel Maze, whereas no data are available on long-term memory in various versions of place avoidance. In an effort to reconcile this issue, rats were administered memantine (5 mg/kg) 30 min before a training session and trained in two different versions of place avoidance. A control group received saline injections. In an active place avoidance task (hereby referred to as Room+Arena-), this place was fixed to distal room cues, whereas cues from the arena were misleading. Performance thus demanded the on-going segregation of information that engages cognitive coordination. Following the Room+Arena- training, rats were trained in another place avoidance task (hereby referred to as Arena+), which requires focusing on substratal and idiothetic cues from the arena. In this version, a to-be-avoided sector rotated along with the arena in darkness that hid the extramaze cues. The rats given memantine avoided better than the control rats in the Room+Arena- task. In the Arena+ task, both groups had problems with acquiring the task. Subsequently, memantine was withdrawn and both groups relearned Room+Arena- avoidance with a new sector position. In this task, no effect of groups was seen. In conclusion, memantine at a therapeutic dose improved performance in a task that required the segregation of spatial stimuli into coherent subsets.

Neural and neuronal discoordination in schizophrenia: From ensembles through networks to symptoms.

Despite the substantial knowledge accumulated by past research, the exact mechanisms of the pathogenesis of schizophrenia and causal treatments still remain unclear. Deficits of cognition and information processing in schizophrenia are today often viewed as the primary and core symptoms of this devastating disorder. These deficits likely result from disruptions in the coordination of neuronal and neural activity. The aim of this review is to bring together convergent evidence of discoordinated brain circuits in schizophrenia at multiple levels of resolution, ranging from principal cells and interneurons, neuronal ensembles and local circuits, to large-scale brain networks. We show how these aberrations could underlie deficits in cognitive control and other higher order cognitive-behavioural functions. Converging evidence from both animal models and patients with schizophrenia is presented in an effort to gain insight into common features of deficits in the brain information processing in this disorder, marked by disruption of several neurotransmitter and signalling systems and severe behavioural outcomes.