Genetic variations in protein expression are implicated in a broad spectrum of common diseases and complex traits but remain less explored compared to mRNA and classical phenotypes. This study systematically analyzed brain proteomes in a rat family using tandem mass tag (TMT)-based quantitative mass spectrometry. We quantified 8,119 proteins across two parental strains (SHR/Olalpcv and BN-Lx/Cub) and 29 HXB/BXH recombinant inbred (RI) strains, identifying 597 proteins with differential expression and 464 proteins linked to cis-acting quantitative trait loci (pQTLs). Proteogenomics identified 95 variant peptides, and sex-specific analyses revealed both shared and distinct cis-pQTLs. We improved the ability to pinpoint candidate genes underlying pQTLs by utilizing the rat pangenome and explored the connections between pQTLs in rats and human disorders. Collectively, this study highlights the value of large proteo-genetic datasets in elucidating protein modulation in the brain and its links to complex central nervous system (CNS) traits.

• Keywords
• Biochemistry, Genetics, Neuroscience,
• Publication type
• Journal Article MeSH

Chemogenetics is a newly developed set of tools that allow for selective manipulation of cell activity. They consist of a receptor mutated irresponsive to endogenous ligands and a synthetic ligand that does not interact with the wild-type receptors. Many different types of these receptors and their respective ligands for inhibiting or excitating neuronal subpopulations were designed in the past few decades. It has been mainly the G-protein coupled receptors (GPCRs) selectively responding to clozapine-N-oxide (CNO), namely Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), that have been employed in research. Chemogenetics offers great possibilities since the activity of the receptors is reversible, inducible on demand by the ligand, and non-invasive. Also, specific groups or types of neurons can be selectively manipulated thanks to the delivery by viral vectors. The effect of the chemogenetic receptors on neurons lasts longer, and even chronic activation can be achieved. That can be useful for behavioral testing. The great advantage of chemogenetic tools is especially apparent in research on brain diseases since they can manipulate whole neuronal circuits and connections between different brain areas. Many psychiatric or other brain diseases revolve around the dysfunction of specific brain networks. Therefore, chemogenetics presents a powerful tool for investigating the underlying mechanisms causing the disease and revealing the link between the circuit dysfunction and the behavioral or cognitive symptoms observed in patients. It could also contribute to the development of more effective treatments.

• MeSH
• Mental Disorders * genetics   metabolism   MeSH
• Clozapine analogs & derivatives   pharmacology   therapeutic use   MeSH
• Humans MeSH
• Neurons metabolism   drug effects   MeSH
• Designer Drugs pharmacology   MeSH
• Receptors, G-Protein-Coupled metabolism   genetics   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Clozapine MeSH
• Designer Drugs MeSH
• Receptors, G-Protein-Coupled MeSH

Stable inter-individual differences in behaviour and personality have been studied for several decades now. The aim of this study was to test the repeatability of behaviour of the Long Evans strain of laboratory rats in order to assess their inter-individual differences. Male laboratory rats (n = 36) were tested in a series of tasks (Open field test, Elevated plus maze test, and modified T-maze test) repeated over time to assess their personality traits. To evaluate the temporal stability of the behaviour, we calculated repeatability estimates of the examined traits. We also checked for a link in behavioural traits across these experiments, which would suggest the existence of a behavioural syndrome. We found stable inter-individual differences in behaviour. Interestingly, no link emerged between the tasks we studied and therefore we did not find support for a behavioural syndrome. The lack of behavioural correlations between these experiments suggests that the results derived from these tasks should be interpreted carefully, as these experiments may measure various behavioural axes. Moreover, the animals habituate to the apparatus. Consequently, behaviour in the Open field test and Elevated plus maze test is not fully consistent and repeatable across subsequent trials.

• MeSH
• Maze Learning MeSH
• Behavior, Animal * MeSH
• Individuality * MeSH
• Rats MeSH
• Personality MeSH
• Rats, Long-Evans MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Before the course of Alzheimer's disease fully manifests itself and largely impairs a patient's cognitive abilities, its progression has already lasted for a considerable time without being noticed. In this project, we mapped the development of spatial orientation impairment in an active place avoidance task-a highly sensitive test for mild hippocampal damage. We tested vision, anxiety and spatial orientation performance at four age levels of 4, 6, 9, and 12 months across male and female TgF-344 AD rats carrying human genes for presenilin-1 and amyloid precursor protein. We found a progressive deterioration of spatial navigation in transgenic animals, beginning already at the age of 4 months, that fully developed at 6 months of age across both male and female groups, compared to their age-matched controls. In addition, we described the gradual vision impairment that was accentuated in females at the age of 12 months. These results indicate a rather early onset of cognitive impairment in the TgF-344 AD Alzheimer's disease model, starting earlier than shown to date, and preceding the reported development of amyloid plaques.

• Keywords
• Alzheimer’s disease, TgF-344 AD, navigation, spatial memory,
• Publication type
• Journal Article MeSH

Evidence from clinical and preclinical studies implicates dysfunction of N-methyl-D-aspartate receptors (NMDARs) in schizophrenia progression and symptoms. We investigated the antipsychotic effect of two neuroactive steroids in an animal model of schizophrenia induced by systemic application of MK-801. The neuroactive steroids differ in their mechanism of action at NMDARs. MS-249 is positive, while PA-Glu is a negative allosteric NMDAR modulator. We hypothesized that the positive NMDA receptor modulator would attenuate deficits caused by MK-801 co-application more effectively than PA-Glu. The rats were tested in a battery of tests assessing spontaneous locomotion, anxiety and cognition. Contrary to our expectations, PA-Glu exhibited a superior antipsychotic effect to MS-249. The performance of MS-249-treated rats in cognitive tests differed depending on the level of stress the rats were exposed to during test sessions. In particular, with the increasing severity of stress exposure, the performance of animals worsened. Our results demonstrate that enhancement of NMDAR function may result in unspecific behavioral responses. Positive NMDAR modulation can influence other neurobiological processes besides memory formation, such as anxiety and response to stress.

• Keywords
• MK-801, anxiety, cognition, neurosteroids, schizophrenia, stress,
• MeSH
• Antipsychotic Agents pharmacology   MeSH
• Bridged Bicyclo Compounds, Heterocyclic metabolism   MeSH
• Behavior, Animal drug effects   MeSH
• Dizocilpine Maleate pharmacology   MeSH
• HEK293 Cells MeSH
• Rats MeSH
• Humans MeSH
• Disease Models, Animal MeSH
• Rats, Long-Evans MeSH
• Rats, Wistar MeSH
• Pregnenolone metabolism   pharmacology   MeSH
• Receptors, N-Methyl-D-Aspartate antagonists & inhibitors   metabolism   MeSH
• Schizophrenia drug therapy   metabolism   MeSH
• Steroids pharmacology   MeSH
• Elevated Plus Maze Test MeSH
• Reflex, Startle drug effects   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Antipsychotic Agents MeSH
• Bridged Bicyclo Compounds, Heterocyclic MeSH
• Dizocilpine Maleate MeSH
• Pregnenolone MeSH
• pregnenolone sulfate MeSH Browser
• Receptors, N-Methyl-D-Aspartate MeSH
• Steroids MeSH
• tert-butylbicyclophosphorothionate MeSH Browser

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.

• Keywords
• 8-OH-DPAT, memantine, memory, obsessive-compulsive disorder, riluzole, spatial learning,
• MeSH
• 8-Hydroxy-2-(di-n-propylamino)tetralin adverse effects   pharmacology   MeSH
• Behavior, Animal drug effects   MeSH
• Rats MeSH
• Memantine pharmacology   MeSH
• Disease Models, Animal MeSH
• Obsessive-Compulsive Disorder * chemically induced   drug therapy   physiopathology   MeSH
• Memory drug effects   MeSH
• Rats, Long-Evans MeSH
• Spatial Learning drug effects   MeSH
• Riluzole pharmacology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 8-Hydroxy-2-(di-n-propylamino)tetralin MeSH
• Memantine MeSH
• Riluzole MeSH

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.

• Keywords
• active place avoidance, hippocampo-prefrontal pathway, muscimol, rotating arena, spatial memory,
• MeSH
• Hippocampus * MeSH
• Rats MeSH
• Muscimol pharmacology   MeSH
• Rats, Long-Evans MeSH
• Prefrontal Cortex MeSH
• Spatial Memory * MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Muscimol MeSH

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.

• Keywords
• autism, chronic bacterial infection, development, lipopolysaccharide, macrocephaly, maternal immune activation, parvalbumin-positive interneurons, prenatal infection, schizophrenia, sex differences,
• MeSH
• Behavior, Animal * MeSH
• Immunohistochemistry MeSH
• Immunomodulation * MeSH
• Interneurons metabolism   MeSH
• Rats MeSH
• Lipopolysaccharides immunology   MeSH
• Maternal Exposure MeSH
• Microglia immunology   metabolism   MeSH
• Brain immunology   metabolism   MeSH
• Parvalbumins metabolism   MeSH
• Sex Factors MeSH
• Social Behavior MeSH
• Pregnancy MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Pregnancy MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Lipopolysaccharides MeSH
• Parvalbumins MeSH

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.

• Keywords
• axon guidance, collapsin response mediator protein 2, dendritic spines, semaphorins, synapse pruning,
• MeSH
• Dendritic Spines MeSH
• Membrane Proteins physiology   MeSH
• Intercellular Signaling Peptides and Proteins genetics   MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Neurons MeSH
• Neuronal Plasticity MeSH
• Autism Spectrum Disorder * MeSH
• Nerve Tissue Proteins genetics   physiology   MeSH
• Semaphorins * MeSH
• Signal Transduction MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• collapsin response mediator protein-2 MeSH Browser
• Membrane Proteins MeSH
• Intercellular Signaling Peptides and Proteins MeSH
• Nerve Tissue Proteins MeSH
• Sema3f protein, mouse MeSH Browser
• Semaphorins * MeSH

The McGill-R-Thy1-APP transgenic rat is an animal model of the familial form of Alzheimer's disease (AD). This model mirrors several neuropathological hallmarks of the disease, including the accumulation of beta-amyloid and the formation of amyloid plaques (in homozygous animals only), neuroinflammation and the gradual deterioration of cognitive functions even prior to plaque formation, although it lacks the tauopathy observed in human victims of AD. The goal of the present study was a thorough characterization of the homozygous model with emphasis on its face validity in several domains of behavior known to be affected in AD patients, including cognitive functions, motor coordination, emotionality, sociability, and circadian activity patterns. On the behavioral level, we found normal locomotor activity in spontaneous exploration, but problems with balance and gait coordination, increased anxiety and severely impaired spatial cognition in 4-7 month old homozygous animals. The profile of social behavior and ultrasonic communication was altered in the McGill rats, without a general social withdrawal. McGill rats also exhibited changes in circadian profile, with a shorter free-running period and increased total activity during the subjective night, without signs of sleep disturbances during the inactive phase. Expression of circadian clock gene Bmal1 was found to be increased in the parietal cortex and cerebellum, while Nr1d1 expression was not changed. The clock-controlled gene Prok2 expression was found to be elevated in the parietal cortex and hippocampus, which might have contributed to the observed changes in circadian phenotype. We conclude that the phenotype in the McGill rat model is not restricted to the cognitive domain, but also includes gait problems, changes in emotionality, social behavior, and circadian profiles. Our findings show that the model should be useful for the development of new therapeutic approaches targeting not only memory decline but also other symptoms decreasing the quality of life of AD patients.

• Keywords
• Alzheimer's disease, amyloid precursor protein, circadian system, cognition, rat, social behavior, transgenic,
• Publication type
• Journal Article MeSH