Aversive olfactory associative memory loses odor specificity over time.

Avoiding associatively learned predictors of danger is crucial for survival. Aversive memories can, however, become counter-adaptive when they are overly generalized to harmless cues and contexts. In a fruit fly odor-electric shock associative memory paradigm, we found that learned avoidance lost its specificity for the trained odor and became general to novel odors within a day of training. We discuss the possible neural circuit mechanisms of this effect and highlight the parallelism to over-generalization of learned fear behavior after an incubation period in rodents and humans, with due relevance for post-traumatic stress disorder.

Distinct contributions of GluA1-containing AMPA receptors of different hippocampal subfields to salience processing, memory and impulse control.

Schizophrenia is associated with a broad range of severe and currently pharmacoresistant cognitive deficits. Prior evidence suggests that hypofunction of AMPA-type glutamate receptors (AMPARs) containing the subunit GLUA1, encoded by GRIA1, might be causally related to impairments of selective attention and memory in this disorder, at least in some patients. In order to clarify the roles of GluA1 in distinct cell populations, we investigated behavioural consequences of selective Gria1-knockout in excitatory neurons of subdivisions of the prefrontal cortex and the hippocampus, assessing sustained attention, impulsivity, cognitive flexibility, anxiety, sociability, hyperactivity, and various forms of short-term memory in mice. We found that virally induced reduction of GluA1 across multiple hippocampal subfields impaired spatial working memory. Transgene-mediated ablation of GluA1 from excitatory cells of CA2 impaired short-term memory for conspecifics and objects. Gria1 knockout in CA3 pyramidal cells caused mild impairments of object-related and spatial short-term memory, but appeared to partially increase social interaction and sustained attention and to reduce motor impulsivity. Our data suggest that reduced hippocampal GluA1 expression-as seen in some patients with schizophrenia-may be a central cause particularly for several short-term memory deficits. However, as impulse control and sustained attention actually appeared to improve with GluA1 ablation in CA3, strategies of enhancement of AMPAR signalling likely require a fine balance to be therapeutically effective across the broad symptom spectrum of schizophrenia.

Delayed-matching-to-position working memory in mice relies on NMDA-receptors in prefrontal pyramidal cells.

A hypofunction of N-methyl-D-aspartate glutamate receptors (NMDARs) has been implicated in the pathogenesis of schizophrenia by clinical and rodent studies. However, to what extent NMDAR-hypofunction in distinct cell-types across the brain causes different symptoms of this disease is largely unknown. One pharmaco-resistant core symptom of schizophrenia is impaired working memory (WM). NMDARs have been suggested to mediate sustained firing in excitatory neurons of the prefrontal cortex (PFC) that might underlie WM storage. However, if NMDAR-hypofunction in prefrontal excitatory neurons may indeed entail WM impairments is unknown. We here investigated this question in mice, in which NMDARs were genetically-ablated in PFC excitatory cells. This cell type-selective NMDAR-hypofunction caused a specific deficit in a delayed-matching-to-position (DMTP) 5-choice-based operant WM task. In contrast, T-maze rewarded alternation and several psychological functions including attention, spatial short-term habituation, novelty-processing, motivation, sociability, impulsivity, and hedonic valuation remained unimpaired at the level of GluN1-hypofunction caused by our manipulation. Our data suggest that a hypofunction of NMDARs in prefrontal excitatory neurons may indeed cause WM impairments, but are possibly not accounting for most other deficits in schizophrenia.

Control of impulsivity by Gi-protein signalling in layer-5 pyramidal neurons of the anterior cingulate cortex.

Pathological impulsivity is a debilitating symptom of multiple psychiatric diseases with few effective treatment options. To identify druggable receptors with anti-impulsive action we developed a systematic target discovery approach combining behavioural chemogenetics and gene expression analysis. Spatially restricted inhibition of three subdivisions of the prefrontal cortex of mice revealed that the anterior cingulate cortex (ACC) regulates premature responding, a form of motor impulsivity. Probing three G-protein cascades with designer receptors, we found that the activation of Gi-signalling in layer-5 pyramidal cells (L5-PCs) of the ACC strongly, reproducibly, and selectively decreased challenge-induced impulsivity. Differential gene expression analysis across murine ACC cell-types and 402 GPCRs revealed that - among Gi-coupled receptor-encoding genes - Grm2 is the most selectively expressed in L5-PCs while alternative targets were scarce. Validating our approach, we confirmed that mGluR2 activation reduced premature responding. These results suggest Gi-coupled receptors in ACC L5-PCs as therapeutic targets for impulse control disorders.

Can N-Methyl-D-Aspartate Receptor Hypofunction in Schizophrenia Be Localized to an Individual Cell Type?

Hypofunction of N-methyl-D-aspartate glutamate receptors (NMDARs), whether caused by endogenous factors like auto-antibodies or mutations, or by pharmacological or genetic manipulations, produces a wide variety of deficits which overlap with-but do not precisely match-the symptom spectrum of schizophrenia. In order to understand how NMDAR hypofunction leads to different components of the syndrome, it is necessary to take into account which neuronal subtypes are particularly affected by it in terms of detrimental functional alterations. We provide a comprehensive overview detailing findings in rodent models with cell type-specific knockout of NMDARs. Regarding inhibitory cortical cells, an emerging model suggests that NMDAR hypofunction in parvalbumin (PV) positive interneurons is a potential risk factor for this disease. PV interneurons display a selective vulnerability resulting from a combination of genetic, cellular, and environmental factors that produce pathological multi-level positive feedback loops. Central to this are two antioxidant mechanisms-NMDAR activity and perineuronal nets-which are themselves impaired by oxidative stress, amplifying disinhibition. However, NMDAR hypofunction in excitatory pyramidal cells also produces a range of schizophrenia-related deficits, in particular maladaptive learning and memory recall. Furthermore, NMDAR blockade in the thalamus disturbs thalamocortical communication, and NMDAR ablation in dopaminergic neurons may provoke over-generalization in associative learning, which could relate to the positive symptom domain. Therefore, NMDAR hypofunction can produce schizophrenia-related effects through an action on various different circuits and cell types.

A simplified microwave-based motion detector for home cage activity monitoring in mice.

BACKGROUND: Locomotor activity of rodents is an important readout to assess well-being and physical health, and is pivotal for behavioral phenotyping. Measuring homecage-activity with standard and cost-effective optical methods in mice has become difficult, as modern housing conditions (e.g. individually ventilated cages, cage enrichment) do not allow constant, unobstructed, visual access. Resolving this issue either makes greater investments necessary, especially if several experiments will be run in parallel, or is at the animals' expense. The purpose of this study is to provide an easy, yet satisfying solution for the behavioral biologist at novice makers level. RESULTS: We show the design, construction and validation of a simplified, low-cost, radar-based motion detector for home cage activity monitoring in mice. In addition we demonstrate that mice which have been selectively bred for low levels of anxiety-related behavior (LAB) have deficits in circadian photoentrainment compared to CD1 control animals. CONCLUSION: In this study we have demonstrated that our proposed low-cost microwave-based motion detector is well-suited for the study of circadian rhythms in mice.