Down Syndrome (DS) in humans is caused by trisomy of chromosome 21 and is marked by prominent difficulties in learning and memory. Decades of research have demonstrated that the hippocampus is a key structure in learning and memory, and recent work with mouse models of DS has suggested differences in hippocampal activity that may be the substrate of these differences. One of the primary functional differences in DS is thought to be an excess of GABAergic innervation from Medial Septum (MS) to the hippocampus. In these experiments, we probe in detail the activity of region CA1 of the hippocampus using in vivo electrophysiology in male Ts65Dn mice, in comparison to their male non-trisomic 2N littermates. We find the spatial properties of place cells in CA1 are normal in Ts65Dn animals. However we find that the phasic relationship of both CA1 place cells and gamma rhythms to theta rhythm in the hippocampus are profoundly altered in these mice. Since the phasic organisation of place cell activity and gamma osc...

Despite significant progress in understanding neural coding, it remains unclear how the coordinated activity of large populations of neurons relates to what an observer actually perceives. Since neurophysiological differences must underlie differences among percepts, differentiation analysis —quantifying distinct patterns of neurophysiological activity—has been proposed as an “inside-out” approach that addresses this question. This methodology contrasts with “outside-in” approaches such as feature tuning and decoding analyses, which are defined in terms of extrinsic experimental variables. Here, we used two-photon calcium imaging in mice of both sexes to systematically survey stimulus-evoked neurophysiological differentiation (ND) in excitatory neuronal populations in layers (L)2/3, L4, and L5 across five visual cortical areas (primary, lateromedial, anterolateral, posteromedial, and anteromedial) in response to naturalistic and phase-scrambled movie stimuli. We find that unscrambled stimuli evoke greater ...

Humans rely on precise proprioceptive feedback from our muscles, which is important in both the acquisition and execution of movements, to perform daily activities. Somatosensory input from the body shapes motor learning through central processes, as demonstrated for tasks using the arm, under active (self-generated) and passive conditions. Presently, we investigated whether passive movement training of the ankle increased proprioceptive acuity (psychophysical experiment) and whether it changed the peripheral proprioceptive afferent signal (microneurography experiment). In the psychophysical experiment, the ankle of 32 healthy human participants was moved passively using pairs of ramp-and-hold movements in different directions. In a pretraining test, participants made judgements about the movement direction in a two-alternative forced choice paradigm. Participants then underwent passive movement training, but only half were cued for learning, where a reference position was signaled by a sound and the parti...

Attention-deficit/hyperactivity disorder (ADHD) in adults is understudied, especially regarding neural mechanisms such as oscillatory control of attention sampling. We report an electroencephalography (EEG) study of such cortical mechanisms, in ADHD-diagnosed adults during administration of Test of Variables of Attention (TOVA), a gold-standard continuous performance test for ADHD that measures the ability to sustain attention and inhibit impulsivity. We recorded 53 adults (28 female, 25 male, aged 18–60), and 18 matched healthy controls, using 128-channel EEG. We analyzed sensor-space features established as neural correlates of attention: timing-sensitivity and phase-synchrony of response activations, and event-related (de)synchronization (ERS/D) of α and θ frequency band activity; in frontal and parietal scalp regions. TOVA test performance significantly distinguished ADHD adults from neurotypical controls, in commission errors, response time variability (RTV) and d′ (response sensitivity). The ADHD gro...

Fear and anxiety can be described as emotional and physical responses to predictable and unpredictable threats. While the amygdala is necessary for context and cued fear conditioning, the bed nucleus of the stria terminalis (BNST) is important for anxiety-like behavior and conditioned responses to diffuse and/or unpredictable threats. However, we still lack knowledge about how the BNST and amygdala nuclei act in coordination. Moreover, the incidence of anxiety disorders and posttraumatic stress disorder (PTSD) is substantially higher in women than in men, but most studies of fear conditioning are conducted in male rodents. Here, we asked whether the BNST and the lateral, basal, and central nuclei of the amygdala are active during the expression of fear conditioning in male and female rats using FOS immunohistochemistry. We first show that the BNST is indeed involved in context fear expression in males, but not in females. The lateral amygdala was active in both sexes during context fear expression. We next...

Parvalbumin (PV)-producing neurons are the largest subpopulation of cortical GABAergic interneurons, which mediate lateral, feedforward, and feedback inhibition in local circuits and modulate the activity of pyramidal neurons. Clarifying the specific connectivity between pyramidal and PV neurons is essential for understanding the role of PV neurons in local circuits. In the present study, we visualized somas and dendrites of PV neurons using transgenic mice in which PV neurons specifically express membrane-targeted GFP, and intracellularly labeled local axons of 26 pyramidal neurons in layers 2–6 in acute slices of the motor-associated cortex from transgenic mice. We mapped morphologically distribution of inputs from a pyramidal neuron to PV neurons based on contact sites (appositions) between the axons from an intracellularly filled pyramidal neuron and the dendrites of PV neurons. Layer 6 corticothalamic (CT)-like pyramidal neurons formed appositions to PV neurons at a significantly higher rate than othe...

Mild traumatic brain injury (mTBI) can initiate complex pathophysiological changes in the brain. Numerous cellular and molecular mechanisms underlying these pathologic changes are altered after injury, including those involved in energy utilization, excitotoxicity, ionic disturbances, and inflammation. It is thought that targeting multiple mechanisms may be necessary to produce meaningful reductions in brain pathology and to improve outcome. Previous studies have reported that the anti-diabetic drug metformin can also affect inflammatory, cell survival, and metabolic outcomes, possibly by acting on multiple targets and/or pathways. We therefore questioned whether metformin treatment can reduce pathology after repeat mild closed head injury (rmCHI) in male C57Bl/6 mice. We found that metformin, administered acutely after each head impact, resulted in markedly reduced white matter damage, astrogliosis, loss of hippocampal parvalbumin neurons, and improved mitochondrial function. In addition, both motor and c...

Exposure of the fetus to alcohol (ethanol) via maternal consumption during pregnancy can result in fetal alcohol spectrum disorders (FASD), hallmarked by long-term physical, behavioral, and intellectual abnormalities. In our preclinical mouse model of FASD, prenatal ethanol exposure disrupts tangential migration of corticopetal GABAergic interneurons (GINs) in the embryonic medial prefrontal cortex (mPFC). We postulated that ethanol perturbed the normal pattern of tangential migration via enhancing GABAA receptor-mediated membrane depolarization that prevails during embryonic development in GABAergic cortical interneurons. However, beyond this, our understanding of the underlying mechanisms is incomplete. Here, we tested the hypothesis that the ethanol-enhanced depolarization triggers downstream an increase in high-voltage-activated nifedipine-sensitive L-type calcium channel (LTCC) activity and provide evidence implicating calcium dynamics in the signaling scheme underlying the migration of embryonic GINs...

Proper somatosensory circuit assembly is critical for processing somatosensory stimuli and for responding accordingly. In comparison to other sensory circuits (e.g., olfactory and visual), somatosensory circuits have unique anatomy and function. However, understanding of somatosensory circuit development lags far behind that of other sensory systems. For example, there are few identified transcription factors required for integration of interneurons into functional somatosensory circuits. Here, as a model, we examine one type of somatosensory interneuron, Even-skipped (Eve) expressing laterally placed interneurons (ELs) of the Drosophila larval nerve cord. Eve is a highly conserved, homeodomain transcription factor known to play a role in cell fate specification and neuronal axon guidance. Because marker genes are often functionally important in the cell types they define, we deleted eve expression specifically from EL interneurons. On the cell biological level, using single neuron labeling, we find eve pl...

Our eyes are constantly in motion and the various kinds of eye movements are closely linked to many aspects of human cognitive processing. Measuring all possible eye movements unobtrusively is not achievable with current methods. Video-based eye-trackers only measure rotational but not translational motion of the eye, require a calibration process relying on the participant’s self-report of accurate fixation, and do not work if vision of the eyeball is blocked. Scleral search coils attach physical weight on the eyeball and also do not measure translation. Here, we describe a novel and fully automated method to use real-time magnetic resonance imaging (MRI) for eye tracking. We achieved a temporal resolution sufficient to measure eye rotations and translations as short as those that occur within a blink and behind a closed eyelid. To demonstrate this method, we measured the full extent of the blink-related eye movement for two individuals, suggesting that the eye approaches a holding position during lid clo...