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

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

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

Muscarinic acetylcholine receptors (mAChRs) have been found to regulate many diverse functions, ranging from motivation and feeding to spatial navigation, an important and widely studied type of cognitive behavior. Systemic administration of non-selective antagonists of mAChRs, such as scopolamine or atropine, have been found to have adverse effects on a vast majority of place navigation tasks. However, many of these results may be potentially confounded by disruptions of functions other than spatial learning and memory. Although studies with selective antimuscarinics point to mutually opposite effects of M1 and M2 receptors, their particular contribution to spatial cognition is still poorly understood, partly due to a lack of truly selective agents. Furthermore, constitutive knock-outs do not always support results from selective antagonists. For modeling impaired spatial cognition, the scopolamine-induced amnesia model still maintains some limited validity, but there is an apparent need for more targeted approaches such as local intracerebral administration of antagonists, as well as novel techniques such as optogenetics focused on cholinergic neurons and chemogenetics aimed at cells expressing metabotropic mAChRs.

• Keywords
• acetylcholine, behavior, biperiden, learning, memory, receptor, rodents, scopolamine,
• Publication type
• Journal Article MeSH
• Review MeSH

Alzheimer's disease (AD) is one of the most serious human, medical, and socioeconomic burdens. Here we tested the hypothesis that a rat model of AD (Samaritan; Taconic Pharmaceuticals, USA) based on the application of amyloid beta42 (Abeta42) and the pro-oxidative substances ferrous sulfate heptahydrate and L-buthionine-(S, R)-sulfoximine, will exhibit cognitive deficits and disruption of the glutamatergic and cholinergic systems in the brain. Behavioral methods included the Morris water maze (MWM; long-term memory version) and the active allothetic place avoidance (AAPA) task (acquisition and reversal), testing spatial memory and different aspects of hippocampal function. Neurochemical methods included testing of the NR1/NR2A/NR2B subunits of NMDA receptors in the frontal cortex and CHT1 transporters in the hippocampus, in both cases in the right and left hemisphere separately. Our results show that Samaritan rats(™) exhibit marked impairment in both the MWM and active place avoidance tasks, suggesting a deficit of spatial learning and memory. Moreover, Samaritan rats exhibited significant changes in NR2A expression and CHT1 activity compared to controls rats, mimicking the situation in patients with early stage AD. Taken together, our results corroborate the hypothesis that Samaritan rats are a promising model of AD in its early stages.

• Keywords
• Alzheimer’s disease, animal model, cognition, hippocampus, learning and memory, neurochemistry of the acetylcholine system, sporadic AD,
• Publication type
• Journal Article MeSH

Mammalian memory is the result of the interaction of millions of neurons in the brain and their coordinated activity. Candidate mechanisms for memory are synaptic plasticity changes, such as long-term potentiation (LTP). LTP is essentially an electrophysiological phenomenon manifested in hours-lasting increase on postsynaptic potentials after synapse tetanization. It is thought to ensure long-term changes in synaptic efficacy in distributed networks, leading to persistent changes in the behavioral patterns, actions and choices, which are often interpreted as the retention of information, i.e., memory. Interestingly, new neurons are born in the mammalian brain and adult hippocampal neurogenesis is proposed to provide a substrate for dynamic and flexible aspects of behavior such as pattern separation, prevention of interference, flexibility of behavior and memory resolution. This work provides a brief review on the memory and involvement of LTP and adult neurogenesis in memory phenomena.

• Keywords
• adult neurogenesis, behavior, hippocampus, learning, memory, synaptic plasticity,
• Publication type
• Journal Article MeSH
• Review MeSH

Flexible behavior in dynamic, real-world environments requires more than static spatial learning and memory. Discordant and unstable cues must be organized in coherent subsets to give rise to meaningful spatial representations. We model this form of cognitive coordination on a rotating arena - Carousel where arena- and room-bound spatial cues are dissociated. Hippocampal neuronal ensemble activity can repeatedly switch between multiple representations of such an environment. Injection of tetrodotoxin into one hippocampus prevents cognitive coordination during avoidance of a stationary room-defined place on the Carousel and increases coactivity of previously unrelated neurons in the uninjected hippocampus. Place avoidance on the Carousel is impaired after systemic administration of non-competitive NMDAr blockers (MK-801) used to model schizophrenia in animals and people. We tested if this effect is due to cognitive disorganization or other effect of NMDAr antagonism such as hyperlocomotion, spatial memory impairment, or general learning deficit. We also examined if the same dose of MK-801 alters patterns of immediate-early gene (IEG) expression in the hippocampus. IEG expression is triggered in neuronal nuclei in a context-specific manner after behavioral exploration and it is used to map activity in neuronal populations. IEG expression is critical for maintenance of synaptic plasticity and memory consolidation. We show that the same dose of MK-801 that impairs spatial coordination of rats on the Carousel also eliminates contextual specificity of IEG expression in hippocampal CA1 ensembles. This effect is due to increased similarity between ensembles activated in different environments, consistent with the idea that it is caused by increased coactivity between neurons, which did not previously fire together. Our data support the proposition of the Hypersynchrony theory that cognitive disorganization in psychosis is due to increased coactivity between unrelated neurons.

• Keywords
• arc, carousel, cognitive coordination, hippocampus, homer 1a, place avoidance, rotating arena, schizophrenia,
• Publication type
• Journal Article MeSH

Inappropriate recollections and responses in stressful conditions are hallmarks of post-traumatic stress disorder and other anxiety and mood disorders, but how stress contributes to the disorders is unclear. Here we show that stress itself reactivates memories even if the memory is unrelated to the stressful experience. Forced-swim stress one day after learning enhanced memory recall. One-day post-learning amnestic treatments were ineffective unless administered soon after the swim, indicating that a stressful experience itself can reactivate unrelated consolidated memories. The swim also triggered inter-hemispheric transfer of a lateralized memory, confirming stress reactivates stable memories. These novel effects of stress on memory required the hippocampus although the memories themselves did not, indicating hippocampus-dependent modulation of extra-hippocampal memories. These findings that a stressful experience itself can activate memory suggest the novel hypothesis that traumatic stress reactivates pre-trauma memories, linking them to memory for the trauma and pathological facilitation of post-traumatic recall.

• MeSH
• Amnesia MeSH
• Hippocampus physiology   MeSH
• Corticosterone analysis   physiology   MeSH
• Rats MeSH
• Models, Animal MeSH
• Memory MeSH
• Swimming MeSH
• Rats, Long-Evans MeSH
• Stress, Psychological MeSH
• Retention, Psychology MeSH
• Stress Disorders, Traumatic MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Corticosterone MeSH