Mutations in neuroligin-3 in male mice impact behavioral flexibility but not relational memory in a touchscreen test of visual transitive inference

Cognitive dysfunction including disrupted behavioral flexibility is central to neurodevelopmental disorders such as Autism Spectrum Disorder (ASD). A cognitive measure that assesses relational memory, and the ability to flexibly assimilate and transfer learned information is transitive inference. Transitive inference is highly conserved across vertebrates and disrupted in cognitive disorders. Here, we examined how mutations in the synaptic cell-adhesion molecule neuroligin-3 (Nlgn3) that have been documented in ASD impact relational memory and behavioral flexibility. We first refined a rodent touchscreen assay to measure visual transitive inference, then assessed two mouse models of Nlgn3 dysfunction (Nlgn3−/y and Nlgn3R451C). Deep analysis of touchscreen behavioral data at a trial level established we could measure trajectories in flexible responding and changes in processing speed as cognitive load increased. We show that gene mutations in Nlgn3 do not disrupt relational memory, but significantly impact flexible responding. Our study presents the first analysis of reaction times in a rodent transitive inference test, highlighting response latencies from the touchscreen system are useful indicators of processing demands or decision-making processes. These findings expand our understanding of how dysfunction of key components of synaptic signaling complexes impact distinct cognitive processes disrupted in neurodevelopmental disorders, and advance our approaches for dissecting rodent behavioral assays to provide greater insights into clinically relevant cognitive symptoms

Interregional compensatory mechanisms of motor functioning in progressing preclinical neurodegeneration.

Understanding brain reserve in preclinical stages of neurodegenerative disorders allows determination of which brain regions contribute to normal functioning despite accelerated neuronal loss. Besides the recruitment of additional regions, a reorganisation and shift of relevance between normally engaged regions are a suggested key mechanism. Thus, network analysis methods seem critical for investigation of changes in directed causal interactions between such candidate brain regions. To identify core compensatory regions, fifteen preclinical patients carrying the genetic mutation leading to Huntington's disease and twelve controls underwent fMRI scanning. They accomplished an auditory paced finger sequence tapping task, which challenged cognitive as well as executive aspects of motor functioning by varying speed and complexity of movements. To investigate causal interactions among brain regions a single Dynamic Causal Model (DCM) was constructed and fitted to the data from each subject. The DCM parameters were analysed using statistical methods to assess group differences in connectivity, and the relationship between connectivity patterns and predicted years to clinical onset was assessed in gene carriers. In preclinical patients, we found indications for neural reserve mechanisms predominantly driven by bilateral dorsal premotor cortex, which increasingly activated superior parietal cortices the closer individuals were to estimated clinical onset. This compensatory mechanism was restricted to complex movements characterised by high cognitive demand. Additionally, we identified task-induced connectivity changes in both groups of subjects towards pre- and caudal supplementary motor areas, which were linked to either faster or more complex task conditions. Interestingly, coupling of dorsal premotor cortex and supplementary motor area was more negative in controls compared to gene mutation carriers. Furthermore, changes in the connectivity pattern of gene carriers allowed prediction of the years to estimated disease onset in individuals. Our study characterises the connectivity pattern of core cortical regions maintaining motor function in relation to varying task demand. We identified connections of bilateral dorsal premotor cortex as critical for compensation as well as task-dependent recruitment of pre- and caudal supplementary motor area. The latter finding nicely mirrors a previously published general linear model-based analysis of the same data. Such knowledge about disease specific inter-regional effective connectivity may help identify foci for interventions based on transcranial magnetic stimulation designed to stimulate functioning and also to predict their impact on other regions in motor-associated networks

Cognition in Stroke Rehabilitation and Recovery Research: Consensus-Based Core Recommendations From the Second Stroke Recovery and Rehabilitation Roundtable

Cognitive impairment is an important target for rehabilitation as it is common following stroke, is associated with reduced quality of life and interferes with motor and other types of recovery interventions. Cognitive function following stroke was identified as an important, but relatively neglected area during the first Stroke Recovery and Rehabilitation Roundtable (SRRR I), leading to a Cognition Working Group being convened as part of SRRR II. There is currently insufficient evidence to build consensus on specific approaches to cognitive rehabilitation. However, we present recommendations on the integration of cognitive assessments into stroke recovery studies generally and define priorities for ongoing and future research for stroke recovery and rehabilitation. A number of promising interventions are ready to be taken forward to trials to tackle the gap in evidence for cognitive rehabilitation. However, to accelerate progress requires that we coordinate efforts to tackle multiple gaps along the whole translational pathway

Cognition in stroke rehabilitation and recovery research: Consensus-based core recommendations from the second Stroke Recovery and Rehabilitation Roundtable

Cognitive impairment is an important target for rehabilitation as it is common following stroke, is associated with reduced quality of life and interferes with motor and other types of recovery interventions. Cognitive function following stroke was identified as an important, but relatively neglected area during the first Stroke Recovery and Rehabilitation Roundtable (SRRR I), leading to a Cognition Working Group being convened as part of SRRR II. There is currently insufficient evidence to build consensus on specific approaches to cognitive rehabilitation. However, we present recommendations on the integration of cognitive assessments into stroke recovery studies generally and define priorities for ongoing and future research for stroke recovery and rehabilitation. A number of promising interventions are ready to be taken forward to trials to tackle the gap in evidence for cognitive rehabilitation. However, to accelerate progress requires that we coordinate efforts to tackle multiple gaps along the whole translational pathway

Haploinsufficiency of EHMT1 improves pattern separation and increases hippocampal cell proliferation

Contains fulltext : 169681.pdf (publisher's version ) (Open Access)Heterozygous mutations or deletions of the human Euchromatin Histone Methyltransferase 1 (EHMT1) gene are the main causes of Kleefstra syndrome, a neurodevelopmental disorder that is characterized by impaired memory, autistic features and mostly severe intellectual disability. Previously, Ehmt1+/- heterozygous knockout mice were found to exhibit cranial abnormalities and decreased sociability, phenotypes similar to those observed in Kleefstra syndrome patients. In addition, Ehmt1+/- knockout mice were impaired at fear extinction and novel- and spatial object recognition. In this study, Ehmt1+/- and wild-type mice were tested on several cognitive tests in a touchscreen-equipped operant chamber to further investigate the nature of learning and memory changes. Performance of Ehmt1+/- mice in the Visual Discrimination &Reversal learning, object-location Paired-Associates learning- and Extinction learning tasks was found to be unimpaired. Remarkably, Ehmt1+/- mice showed enhanced performance on the Location Discrimination test of pattern separation. In line with improved Location Discrimination ability, an increase in BrdU-labelled cells in the subgranular zone of the dentate gyrus was observed. In conclusion, reduced levels of EHMT1 protein in Ehmt1+/- mice does not result in general learning deficits in a touchscreen-based battery, but leads to increased adult cell proliferation in the hippocampus and enhanced pattern separation ability

Physical activity to improve cognition in older adults: can physical activity programs enriched with cognitive challenges enhance the effects? A systematic review and meta-analysis

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Absence of Ca2+-stimulated adenylyl cyclases leads to reduced synaptic plasticity and impaired experience-dependent fear memory

Ca2+-stimulated adenylyl cyclase (AC) 1 and 8 are two genes that have been shown to play critical roles in fear memory. AC1 and AC8 couple neuronal activity and intracellular Ca2+ increases to the production of cyclic adenosine monophosphate and are localized synaptically, suggesting that Ca2+-stimulated ACs may modulate synaptic plasticity. Here, we first established that Ca2+-stimulated ACs modulate protein markers of synaptic activity at baseline and after learning. Primary hippocampal cell cultures showed that AC1/AC8 double-knockout (DKO) mice have reduced SV2, a synaptic vesicle protein, abundance along their dendritic processes, and this reduction can be rescued through lentivirus delivery of AC8 to the DKO cells. Additionally, phospho-synapsin, a protein implicated in the regulation of neurotransmitter release at the synapse, is decreased in vivo 1 h after conditioned fear (CF) training in DKO mice. Importantly, additional experiments showed that long-term potentiation deficits present in DKO mice are rescued by acutely replacing AC8 in the forebrain, further supporting the idea that Ca2+-stimulated AC activity is a crucial modulator of synaptic plasticity. Previous studies have demonstrated that memory is continually modulated by gene–environment interactions. The last set of experiments evaluated the effects of knocking out AC1 and AC8 genes on experience-dependent changes in CF memory. We showed that the strength of CF memory in wild-type mice is determined by previous environment, minimal or enriched, whereas memory in DKO mice is unaffected. Thus, overall these results show that AC1 and AC8 modulate markers of synaptic activity and help integrate environmental information to modulate fear memory

Arc requires PSD95 for assembly into postsynaptic complexes involved with neural dysfunction and intelligence

Arc is an activity-regulated neuronal protein, but little is known about its interactions, assembly into multiprotein complexes, and role in human disease and cognition. We applied an integrated proteomic and genetic strategy by targeting a tandem affinity purification (TAP) tag and Venus fluorescent protein into the endogenous Arc gene in mice. This allowed biochemical and proteomic characterization of native complexes in wild-type and knockout mice. We identified many Arc-interacting proteins, of which PSD95 was the most abundant. PSD95 was essential for Arc assembly into 1.5-MDa complexes and activity-dependent recruitment to excitatory synapses. Integrating human genetic data with proteomic data showed that Arc-PSD95 complexes are enriched in schizophrenia, intellectual disability, autism, and epilepsy mutations and normal variants in intelligence. We propose that Arc-PSD95 postsynaptic complexes potentially affect human cognitive function