Maternally derived copy number gains of human chromosome 15q11.2-q13.3 (Dup15q syndrome or Dup15q) cause intellectual disability, epilepsy, developmental delay, hypotonia, speech impairments, and minor dysmorphic features. Dup15q syndrome is one of the most common and penetrant chromosomal abnormalities observed in individuals with autism spectrum disorder (ASD). Although ∼40 genes are located in the 15q11.2-q13.3 region, overexpression of the ubiquitin-protein E3A ligase (UBE3A) gene is thought to be the predominant molecular cause of the phenotypes observed in Dup15q syndrome. The UBE3A gene demonstrates maternal-specific expression in neurons and loss of maternal UBE3A causes Angelman syndrome, a neurodevelopmental disorder with some overlapping neurological features to Dup15q. To directly test the hypothesis that overexpression of UBE3A is an important underlying molecular cause of neurodevelopmental dysfunction, we developed and characterized a mouse overexpressing Ube3a isoform 2 in excitatory neurons. Ube3a isoform 2 is conserved between mouse and human and known to play key roles in neuronal function. Transgenic mice overexpressing Ube3a isoform 2 in excitatory forebrain neurons exhibited increased anxiety-like behaviors, learning impairments, and reduced seizure thresholds. However, these transgenic mice displayed normal social approach, social interactions, and repetitive motor stereotypies that are relevant to ASD. Reduced forebrain, hippocampus, striatum, amygdala, and cortical volume were also observed. Altogether, these findings show neuronal overexpression of Ube3a isoform 2 causes phenotypes translatable to neurodevelopmental disorders.
SHANK3 is a synaptic scaffolding protein localized in the postsynaptic density and has a crucial role in synaptogenesis and neural physiology. Deletions and point mutations in SHANK3 cause Phelan–McDermid Syndrome (PMS), and have also been implicated in autism spectrum disorder (ASD) and intellectual disabilities, leading to the hypothesis that reduced SHANK3 expression impairs basic brain functions that are important for social communication and cognition. Several mouse models of Shank3 deletions have been generated, varying in the specific domain deleted. Here we report impairments in cognitive function in mice heterozygous for exon 13–16 (coding for the PDZ domain) deletion. The touchscreen pairwise discrimination task was chosen by virtue of its: (a) conceptual and technical similarities to the Cambridge Neuropsychological Test Automated Battery (CANTAB) and NIH Toolbox Cognition Battery used for testing cognitive functions in humans, (b) minimal demand on motor abilities, and (c) capability to measure many aspects of learning and memory and complex cognitive functions, including cognitive flexibility. The similarity between our mouse tasks and human cognitive assays means a high translational validity in future intervention studies using preclinical models. Our study revealed that Shank3B heterozygous mice (+/–) were slower to reach criterion in the pairwise visual discrimination task, and exhibited trends toward making more errors (first trial errors) and more correction errors than wildtype mice (+/+). Open field activity was normal in +/–, ruling out hypo- or hyperactivity as potential confounds in the touchscreen test. Sociability in the three chamber test was also normal in both +/+ and +/–. These results indicate a deficit in discrimination learning in the Shank3B model of PMS and ASD, suggesting that this mouse model is a useful preclinical tool for studying neurobiological mechanisms behind cognitive impairments in PMS and ASD. The current findings are the starting point for our future research in which we will investigate multiple domains of cognition and explore pharmacological interventions.
The default-mode network (DMN) in humans consists of a set of brain regions that, as measured with functional magnetic resonance imaging (fMRI), show both intrinsic correlations with each other and suppression during externally oriented tasks. Resting-state fMRI studies have previously identified similar patterns of intrinsic correlations in overlapping brain regions in rodents (A29C/posterior cingulate cortex, parietal cortex, and medial temporal lobe structures). However, due to challenges with performing rodent behavior in an MRI machine, it is still unclear whether activity in rodent DMN regions are suppressed during externally oriented visual tasks. Using distributed local field potential measurements in rats, we have discovered that activity in DMN brain regions noted above show task-related suppression during an externally oriented visual task at alpha and low beta-frequencies. Interestingly, this suppression (particularly in posterior cingulate cortex) was linked with improved performance on the task. Using electroencephalography recordings from a similar task in humans, we identified a similar suppression of activity in posterior cingulate cortex at alpha/low beta-frequencies. Thus, we have identified a common electrophysiological marker of DMN suppression in both rodents and humans. This observation paves the way for future studies using rodents to probe circuit-level functioning of DMN function. Significance Here we show that alpha/beta frequency oscillations in rats show key features of DMN activity, including intrinsic correlations between DMN brain regions, task-related suppression, and interference with attention/decision-making. We found similar task-related suppression at alpha/low beta-frequencies of DMN activity in humans.
A key aspect of behavioral inhibition is the ability to wait before acting. Failures in this form of inhibition result in impulsivity and are commonly observed in various neuropsychiatric disorders. Prior evidence has implicated medial frontal cortex, motor cortex, orbitofrontal cortex (OFC), and ventral striatum in various aspects of inhibition. Here, using distributed recordings of brain activity [with local-field potentials (LFPs)] in rodents, we identified oscillatory patterns of activity linked with action and inhibition. Low-frequency (δ) activity within motor and premotor circuits was observed in two distinct networks, the first involved in cued, sensory-based responses and the second more generally in both cued and delayed actions. By contrast, θ activity within prefrontal and premotor regions (medial frontal cortex, OFC, ventral striatum, and premotor cortex) was linked with inhibition. Connectivity at θ frequencies was observed within this network of brain regions. Interestingly, greater connectivity between primary motor cortex (M1) and other motor regions was linked with greater impulsivity, whereas greater connectivity between M1 and inhibitory brain regions (OFC, ventral striatum) was linked with improved inhibition and diminished impulsivity. We observed similar patterns of activity on a parallel task in humans: low-frequency activity in sensorimotor cortex linked with action, θ activity in OFC/ventral prefrontal cortex (PFC) linked with inhibition. Thus, we show that δ and θ oscillations form distinct large-scale networks associated with action and inhibition, respectively.
Rodent models of cognitive behavior have greatly contributed to our understanding of human neuropsychiatric disorders. However, to elucidate the neurobiological underpinnings of such disorders or impairments, animal models are more useful when paired with methods for measuring brain function in awake, behaving animals. Standard tools used for systems-neuroscience level investigations are not optimized for large-scale and high-throughput behavioral battery testing due to various factors including cost, time, poor longevity, and selective targeting limited to measuring only a few brain regions at a time. Here we describe two different “user-friendly” methods for building extracellular electrophysiological probes that can be used to measure either single units or local field potentials in rats performing cognitive tasks. Both probe designs leverage several readily available, yet affordable, commercial products to facilitate ease of production and offer maximum flexibility in terms of brain-target locations that can be scalable (32–64 channels) based on experimental needs. Our approach allows neural activity to be recorded simultaneously with behavior and compared between micro (single unit) and more macro (local field potentials) levels of brain activity in order to gain a better understanding of how local brain regions and their connected networks support cognitive functions in rats. We believe our novel probe designs make collecting electrophysiology data easier and will begin to fill the gap in knowledge between basic and clinical research.
AIMTo investigate the acute effects of sinusoidal and stochastic resonance partial-body vibration in sitting position, including muscle activity, heart rate variability, balance and flexibility.METHODSFifty healthy participants were assigned randomly to two training conditions: A sinusoidal partial-body vibration (SIN, 8 Hz) or a stochastic resonance partial-body vibration (STOCH, 8 ± 2 Hz). For baseline assessment participants sat on the vibration platform without vibration. Both training conditions consisted of five series of a one-minute vibration training and a one-minute break between them. In this experimental study surface electromyography (EMG) of the erector spinae (ES), one of the back muscles, and heart rate variability (HRV) was measured at baseline and during training. Balance and flexibility were assessed at baseline and immediately after training. Balance was measured with the modified star excursion balance test (mSEBT) and flexibility was assessed through the modified fingertip-to-floor method (mFTF).RESULTSPaired sample t-test showed a significant increase in balance that was restricted to STOCH (t = -2.22, P = 0.018; SIN: t = -0.09, P = 0.466). An increase in flexibility was also restricted to STOCH (t = 2.65, P = 0.007; SIN: t = 1.41, P = 0.086). There was no significant change of muscle activity in the ES-EMG in STOCH or SIN conditions. In both training conditions, HRV decreased significantly, but remained in a low-load range (STOCH: t = 2.89, P = 0.004; SIN: t = 2.55, P = 0.009).CONCLUSIONIn sitting position, stochastic resonance partial-body vibration can improve balance and flexibility while cardiovascular load is low. STOCH can be a valuable training option to people who are unable to stand (e.g., people, who are temporarily wheelchair-bound).
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