SYNGAP1 deficiency disrupts synaptic neoteny in xenotransplanted human cortical neurons in vivo.

Human brain ontogeny is characterized by a considerably prolonged neotenic development of cortical neurons and circuits. Neoteny is thought to be essential for the acquisition of advanced cognitive functions, which are typically altered in intellectual disability (ID) and autism spectrum disorders (ASDs). Human neuronal neoteny could be disrupted in some forms of ID and/or ASDs, but this has never been tested. Here, we use xenotransplantation of human cortical neurons into the mouse brain to model SYNGAP1 haploinsufficiency, one of the most prevalent genetic causes of ID/ASDs. We find that SYNGAP1-deficient human neurons display strong acceleration of morphological and functional synaptic formation and maturation alongside disrupted synaptic plasticity. At the circuit level, SYNGAP1-haploinsufficient neurons display precocious acquisition of responsiveness to visual stimulation months ahead of time. Our findings indicate that SYNGAP1 is required cell autonomously for human neuronal neoteny, providing novel links between human-specific developmental mechanisms and ID/ASDs.

Studying human neural function in vivo at the cellular level: Chasing chimeras?

Despite its importance to understanding human brain (dys)function, it has remained challenging to study human neurons in vivo. Recent approaches, using transplantation of human cortical neurons into the rodent brain, offer new prospects for the study of human neural function and disease in vivo, from molecular to circuit levels.

Astrocyte calcium dysfunction causes early network hyperactivity in Alzheimer's disease.

Dysfunctions of network activity and functional connectivity (FC) represent early events in Alzheimer's disease (AD), but the underlying mechanisms remain unclear. Astrocytes regulate local neuronal activity in the healthy brain, but their involvement in early network hyperactivity in AD is unknown. We show increased FC in the human cingulate cortex several years before amyloid deposition. We find the same early cingulate FC disruption and neuronal hyperactivity in AppNL-F mice. Crucially, these network disruptions are accompanied by decreased astrocyte calcium signaling. Recovery of astrocytic calcium activity normalizes neuronal hyperactivity and FC, as well as seizure susceptibility and day/night behavioral disruptions. In conclusion, we show that astrocytes mediate initial features of AD and drive clinically relevant phenotypes.

Diversity of spatiotemporal coding reveals specialized visual processing streams in the mouse cortex.

The cerebral cortex contains diverse neural representations of the visual scene, each enabling distinct visual and spatial abilities. However, the extent to which representations are distributed or segregated across cortical areas remains poorly understood. By determining the spatial and temporal responses of >30,000 layer 2/3 pyramidal neurons, we characterize the functional organization of parallel visual streams across eight areas of the mouse cortex. While dorsal and ventral areas form complementary representations of spatiotemporal frequency, motion speed, and spatial patterns, the anterior and posterior dorsal areas show distinct specializations for fast and slow oriented contrasts. At the cellular level, while diverse spatiotemporal tuning lies along a continuum, oriented and non-oriented spatial patterns are encoded by distinct tuning types. The identified tuning types are present across dorsal and ventral streams. The data underscore the highly specific and highly distributed nature of visual cortical representations, which drives specialization of cortical areas and streams.

Face categorization and behavioral templates in rats.

Rodents have become a popular model in vision science. It is still unclear how vision in rodents relates to primate vision when it comes to complex visual tasks. Here we report on the results of training rats in a face-categorization and generalization task. Additionally, the Bubbles paradigm is used to determine the behavioral templates of the animals. We found that rats are capable of face categorization and can generalize to previously unseen exemplars. Performance is affected-but remains above chance-by stimulus modifications such as upside-down and contrast-inverted stimuli. The behavioral templates of the rats overlap with a pixel-based template, with a bias toward the upper left parts of the stimuli. Together, these findings significantly expand the evidence about the extent to which rats learn complex visual-categorization tasks.

Xenotransplanted Human Cortical Neurons Reveal Species-Specific Development and Functional Integration into Mouse Visual Circuits.

How neural circuits develop in the human brain has remained almost impossible to study at the neuronal level. Here, we investigate human cortical neuron development, plasticity, and function using a mouse/human chimera model in which xenotransplanted human cortical pyramidal neurons integrate as single cells into the mouse cortex. Combined neuronal tracing, electrophysiology, and in vivo structural and functional imaging of the transplanted cells reveal a coordinated developmental roadmap recapitulating key milestones of human cortical neuron development. The human neurons display a prolonged developmental timeline, indicating the neuron-intrinsic retention of juvenile properties as an important component of human brain neoteny. Following maturation, human neurons in the visual cortex display tuned, decorrelated responses to visual stimuli, like mouse neurons, demonstrating their capacity for physiological synaptic integration in host cortical circuits. These findings provide new insights into human neuronal development and open novel avenues for the study of human neuronal function and disease. VIDEO ABSTRACT.

Long-term enzyme replacement therapy improves neurocognitive functioning and hippocampal synaptic plasticity in immune-tolerant alpha-mannosidosis mice.

Alpha-mannosidosis is a glycoproteinosis caused by deficiency of lysosomal acid alpha-mannosidase (LAMAN), which markedly affects neurons of the central nervous system (CNS), and causes pathognomonic intellectual dysfunction in the clinical condition. Cognitive improvement consequently remains a major therapeutic objective in research on this devastating genetic error. Immune-tolerant LAMAN knockout mice were developed to evaluate the effects of enzyme replacement therapy (ERT) by prolonged administration of recombinant human enzyme. Biochemical evidence suggested that hippocampus may be one of the brain structures that benefits most from long-term ERT. In the present functional study, ERT was initiated in 2-month-old immune-tolerant alpha-mannosidosis mice and continued for 9months. During the course of treatment, mice were trained in the Morris water maze task to assess spatial-cognitive performance, which was related to synaptic plasticity recordings and hippocampal histopathology. Long-term ERT reduced primary substrate storage and neuroinflammation in hippocampus, and improved spatial learning after mid-term (10weeks+) and long-term (30weeks+) treatment. Long-term treatment substantially improved the spatial-cognitive abilities of alpha-mannosidosis mice, whereas the effects of mid-term treatment were more modest. Detailed analyses of spatial memory and spatial-cognitive performance indicated that even prolonged ERT did not restore higher cognitive abilities to the level of healthy mice. However, it did demonstrate marked therapeutic effects that coincided with increased synaptic connectivity, reflected by improvements in hippocampal CA3-CA1 long-term potentiation (LTP), expression of postsynaptic marker PSD-95 as well as postsynaptic density morphology. These experiments indicate that long-term ERT may hold promise, not only for the somatic defects of alpha-mannosidosis, but also to alleviate cognitive impairments of the disorder.

Comparison of the spatial-cognitive functions of dorsomedial striatum and anterior cingulate cortex in mice.

Neurons in anterior cingulate cortex (aCC) project to dorsomedial striatum (DMS) as part of a corticostriatal circuit with putative roles in learning and other cognitive functions. In the present study, the spatial-cognitive importance of aCC and DMS was assessed in the hidden-platform version of the Morris water maze (MWM). Brain lesion experiments that focused on areas of connectivity between these regions indicated their involvement in spatial cognition. MWM learning curves were markedly delayed in DMS-lesioned mice in the absence of other major functional impairments, whereas there was a more subtle, but still significant influence of aCC lesions. Lesioned mice displayed impaired abilities to use spatial search strategies, increased thigmotaxic swimming, and decreased searching in the proximity of the escape platform. Additionally, aCC and DMS activity was compared in mice between the early acquisition phase (2 and 3 days of training) and the over-trained high-proficiency phase (after 30 days of training). Neuroplasticity-related expression of the immediate early gene Arc implicated both regions during the goal-directed, early phases of spatial learning. These results suggest the functional involvement of aCC and DMS in processes of spatial cognition that model associative cortex-dependent, human episodic memory abilities.

Neural Representations of Natural and Scrambled Movies Progressively Change from Rat Striate to Temporal Cortex.

In recent years, the rodent has come forward as a candidate model for investigating higher level visual abilities such as object vision. This view has been backed up substantially by evidence from behavioral studies that show rats can be trained to express visual object recognition and categorization capabilities. However, almost no studies have investigated the functional properties of rodent extrastriate visual cortex using stimuli that target object vision, leaving a gap compared with the primate literature. Therefore, we recorded single-neuron responses along a proposed ventral pathway in rat visual cortex to investigate hallmarks of primate neural object representations such as preference for intact versus scrambled stimuli and category-selectivity. We presented natural movies containing a rat or no rat as well as their phase-scrambled versions. Population analyses showed increased dissociation in representations of natural versus scrambled stimuli along the targeted stream, but without a clear preference for natural stimuli. Along the measured cortical hierarchy the neural response seemed to be driven increasingly by features that are not V1-like and destroyed by phase-scrambling. However, there was no evidence for category selectivity for the rat versus nonrat distinction. Together, these findings provide insights about differences and commonalities between rodent and primate visual cortex.

Impulsivity, decreased social exploration, and executive dysfunction in a mouse model of frontotemporal dementia.

Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disorder, a major subset of which is characterized by the accumulation of abnormal forms of the protein tau, leading to impairments in motor functions as well as language and behavioral alterations. Tau58-2/B mice express human tau with the P301S mutation found in familial forms of FTLD in neurons. By assessing three age cohorts of Tau58-2/B mice in a comprehensive behavioral test battery, we found that the tauopathy animals showed age-dependent signs of impulsivity, decreased social exploration and executive dysfunction. The deficit in executive function was first limited to decreased spatial working memory, but with aging this was extended to impaired instrumental short-term memory. Tau pathology was prominent in brain regions underlying these behaviors. Thus, Tau-58-2/B mice recapitulate neurological deficits of the behavioral variant of frontotemporal dementia (bvFTD), presenting them as a suitable model to test therapeutic interventions for the amelioration of this variant.

Inability to acquire spatial information and deploy spatial search strategies in mice with lesions in dorsomedial striatum.

Dorsal striatum has been shown to contribute to spatial learning and memory, but the role of striatal subregions in this important aspect of cognitive functioning remains unclear. Moreover, the spatial-cognitive mechanisms that underlie the involvement of these regions in spatial navigation have scarcely been studied. We therefore compared spatial learning and memory performance in mice with lesions in dorsomedial (DMS) and dorsolateral striatum (DLS) using the hidden-platform version of the Morris water maze (MWM) task. Compared to sham-operated controls, animals with DMS damage were impaired during MWM acquisition training. These mice displayed delayed spatial learning, increased thigmotaxis, and increased search distance to the platform, in the absence of major motor dysfunction, working memory defects or changes in anxiety or exploration. They failed to show a preference for the target quadrant during probe trials, which further indicates that spatial reference memory was impaired in these animals. Search strategy analysis moreover demonstrated that DMS-lesioned mice were unable to deploy cognitively advanced spatial search strategies. Conversely, MWM performance was barely affected in animals with lesions in DLS. In conclusion, our results indicate that DMS and DLS display differential functional involvement in spatial learning and memory. Our results show that DMS, but not DLS, is crucial for the ability of mice to acquire spatial information and their subsequent deployment of spatial search strategies. These data clearly identify DMS as a crucial brain structure for spatial learning and memory, which could explain the occurrence of neurocognitive impairments in brain disorders that affect the dorsal striatum.

Nxf7 deficiency impairs social exploration and spatio-cognitive abilities as well as hippocampal synaptic plasticity in mice.

Nuclear RNA export factors (NXF) are conserved in all metazoans and are deemed essential for shuttling RNA across the nuclear envelope and other post-transcriptional processes (such as mRNA metabolism, storage and stability). Disruption of human NXF5 has been implicated in intellectual and psychosocial disabilities. In the present report, we use recently described Nxf7 knockout (KO) mice as an experimental model to analyze in detail the behavioral consequences of clinical NXF5 deficiency. We examined male Nxf7 KO mice using an extended cognitive and behavioral test battery, and recorded extracellular field potentials in the hippocampal CA1 region. We observed various cognitive and behavioral changes including alterations in social exploration, impaired spatial learning and spatio-cognitive abilities. We also defined a new experimental paradigm to discriminate search strategies in Morris water maze and showed significant differences between Nxf7 KO and control animals. Furthermore, while we observed no difference in a nose poke suppression in an conditioned emotional response (CER) protocol, Nxf7 KO mice were impaired in discriminating between differentially reinforced cues in an auditory fear conditioning protocol. This distinct neurocognitive phenotype was accompanied by impaired hippocampal Long-term potentiation (LTP), while long-term depression (LTD) was not affected by Nxf7 deficiency. Our data demonstrate that disruption of murine Nxf7 leads to behavioral phenotypes that may relate to the intellectual and social deficits in patients with NXF5 deficiency.

Neural discriminability in rat lateral extrastriate cortex and deep but not superficial primary visual cortex correlates with shape discriminability.

Recent studies have revealed a surprising degree of functional specialization in rodent visual cortex. It is unknown to what degree this functional organization is related to the well-known hierarchical organization of the visual system in primates. We designed a study in rats that targets one of the hallmarks of the hierarchical object vision pathway in primates: selectivity for behaviorally relevant dimensions. We compared behavioral performance in a visual water maze with neural discriminability in five visual cortical areas. We tested behavioral discrimination in two independent batches of six rats using six pairs of shapes used previously to probe shape selectivity in monkey cortex (Lehky and Sereno, 2007). The relative difficulty (error rate) of shape pairs was strongly correlated between the two batches, indicating that some shape pairs were more difficult to discriminate than others. Then, we recorded in naive rats from five visual areas from primary visual cortex (V1) over areas LM, LI, LL, up to lateral occipito-temporal cortex (TO). Shape selectivity in the upper layers of V1, where the information enters cortex, correlated mostly with physical stimulus dissimilarity and not with behavioral performance. In contrast, neural discriminability in lower layers of all areas was strongly correlated with behavioral performance. These findings, in combination with the results from Vermaercke et al. (2014b), suggest that the functional specialization in rodent lateral visual cortex reflects a processing hierarchy resulting in the emergence of complex selectivity that is related to behaviorally relevant stimulus differences.

Visual categorization of natural movies by rats.

Visual categorization of complex, natural stimuli has been studied for some time in human and nonhuman primates. Recent interest in the rodent as a model for visual perception, including higher-level functional specialization, leads to the question of how rodents would perform on a categorization task using natural stimuli. To answer this question, rats were trained in a two-alternative forced choice task to discriminate movies containing rats from movies containing other objects and from scrambled movies (ordinate-level categorization). Subsequently, transfer to novel, previously unseen stimuli was tested, followed by a series of control probes. The results show that the animals are capable of acquiring a decision rule by abstracting common features from natural movies to generalize categorization to new stimuli. Control probes demonstrate that they did not use single low-level features, such as motion energy or (local) luminance. Significant generalization was even present with stationary snapshots from untrained movies. The variability within and between training and test stimuli, the complexity of natural movies, and the control experiments and analyses all suggest that a more high-level rule based on more complex stimulus features than local luminance-based cues was used to classify the novel stimuli. In conclusion, natural stimuli can be used to probe ordinate-level categorization in rats.

Functional specialization in rat occipital and temporal visual cortex.

Recent studies have revealed a surprising degree of functional specialization in rodent visual cortex. Anatomically, suggestions have been made about the existence of hierarchical pathways with similarities to the ventral and dorsal pathways in primates. Here we aimed to characterize some important functional properties in part of the supposed "ventral" pathway in rats. We investigated the functional properties along a progression of five visual areas in awake rats, from primary visual cortex (V1) over lateromedial (LM), latero-intermediate (LI), and laterolateral (LL) areas up to the newly found lateral occipito-temporal cortex (TO). Response latency increased >20 ms from areas V1/LM/LI to areas LL and TO. Orientation and direction selectivity for the used grating patterns increased gradually from V1 to TO. Overall responsiveness and selectivity to shape stimuli decreased from V1 to TO and was increasingly dependent upon shape motion. Neural similarity for shapes could be accounted for by a simple computational model in V1, but not in the other areas. Across areas, we find a gradual change in which stimulus pairs are most discriminable. Finally, tolerance to position changes increased toward TO. These findings provide unique information about possible commonalities and differences between rodents and primates in hierarchical cortical processing.

SSP-002392, a new 5-HT4 receptor agonist, dose-dependently reverses scopolamine-induced learning and memory impairments in C57Bl/6 mice.

5-HT4 receptors (5-HT4R) are suggested to affect learning and memory processes. Earlier studies have shown that animals treated with 5-HT4R agonists, often with limited selectivity, show improved learning and memory with retention memory often being assessed immediately after or within 24 h after the last training session. In this study, we characterized the effect of pre-training treatment with the selective 5-HT4R agonist SSP-002392 on memory acquisition and the associated long-term memory retrieval in animal models of impaired cognition. Pre-training treatment with SSP-002392 (0.3 mg/kg, 1.5 mg/kg and 7.5 mg/kg p.o.) dose-dependently inhibited the cognitive deficits induced by scopolamine (0.5 mg/kg s.c.) in two different behavioral tasks: passive avoidance and Morris water maze. In the Morris water maze, spatial learning was significantly improved after treatment with SSP-002392 translating in an accelerated and more efficient localization of the hidden platform compared to scopolamine-treated controls. Moreover, retention memory was assessed 24 h (passive avoidance) and 72 h (Morris water maze) after the last training session of cognitive-impaired animals and this was significantly improved in animals treated with SSP-002392 prior to the training sessions. Furthermore, the effects of SSP-002392 were comparable to galanthamine hydrobromide. We conclude that SSP-002392 has potential as a memory-enhancing compound.

More complex brains are not always better: rats outperform humans in implicit category-based generalization by implementing a similarity-based strategy.

Generalization from previous experiences to new situations is a hallmark of intelligent behavior and a prerequisite for category learning. It has been proposed that category learning in humans relies on multiple brain systems that compete with each other, including an explicit, rule-based system and an implicit system. Given that humans are biased to follow rule-based strategies, a counterintuitive prediction of this model is that other animals, in which this rule-based system is less developed, might generalize better to new stimuli in implicit category-learning tasks that are not rule-based. To test this prediction, rats and humans were trained in rule-based and information-integration category-learning tasks with visual stimuli. The generalization performance of rats and humans was equal in rule-based categorization, but rats outperformed humans on generalization in the information-integration task. The performance of rats was consistent with a nondimensional, similarity-based categorization strategy. These findings illustrate through a comparative approach that the bias toward rule-based strategies can impede humans' performance on generalization tasks.

Dose-dependent improvements in learning and memory deficits in APPPS1-21 transgenic mice treated with the orally active Aß toxicity inhibitor SEN1500.

In the Alzheimer's disease (AD) brain, accumulation of Aß1-42 peptides is suggested to initiate a cascade of pathological events. To date, no treatments are available that can reverse or delay AD-related symptoms in patients. In the current study, we introduce a new Aß toxicity inhibitor, SEN1500, which in addition to its block effect on Aß1-42 toxicity in synaptophysin assays, can be administered orally and cross the blood-brain barrier without adverse effects in mice. In a different set of animals, APPPS1-21 mice were fed with three different doses of SEN1500 (1 mg/kg, 5 mg/kg and 20 mg/kg) for a period of 5 months. Cognition was assessed in a variety of behavioral tests (Morris water maze, social recognition, conditioned taste aversion and passive avoidance). Results suggest a positive effect on cognition with 20 mg/kg SEN1500 compared to control APPPS1-21 mice. However, no changes in soluble or insoluble Aß1-40 and Aß1-42 were detected in the brains of SEN1500-fed mice. SEN1500 also attenuated the effect of Aß1-42 on synaptophysin levels in mouse cortical neurons, which indicated that the compound blocked the synaptic toxicity of Aß1-42. In vitro and in vivo effects presented here suggest that SEN1500 could be an interesting AD therapeutic.

Progressive age-related cognitive decline in tau mice.

Age-related cognitive decline and neurodegenerative diseases are a growing challenge for society. Accumulation of tau pathology has been proposed to partially contribute to these impairments. This study provides a behavioral characterization during aging of transgenic mice bearing tau mutations. THY-Tau22 mice were evaluated at ages wherein tau neuropathology in this transgenic mouse model is low (3-4 months), moderate (6-7 months), or extensive (>9 months). Spatial memory was found to be impaired only after 9 months of age in THY-Tau22 mice, whereas non-spatial memory was affected as early as 6 months, appearing to offer an opportunity for assessing potential therapeutic agents in attenuating or preventing tauopathies through modulation of tau kinetics.