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...

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...

Following traumatic brain injury (TBI), cognitive impairments manifest through interactions between microscopic and macroscopic changes. On the microscale, a neurometabolic cascade alters neurotransmission, while on the macroscale diffuse axonal injury impacts the integrity of long-range connections. Large-scale brain network modeling allows us to make predictions across these spatial scales by integrating neuroimaging data with biophysically based models to investigate how microscale changes invisible to conventional neuroimaging influence large-scale brain dynamics. To this end, we analyzed structural and functional neuroimaging data from a well characterized sample of 44 adult TBI patients recruited from a regional trauma center, scanned at 1–2 weeks postinjury, and with follow-up behavioral outcome assessed 6 months later. Thirty-six age-matched healthy adults served as comparison participants. Using The Virtual Brain, we fit simulations of whole-brain resting-state functional MRI to the empirical stat...

Parvalbumin-positive (Pvalb+) and somatostatin-positive (Sst+) cells are the two largest subgroups of inhibitory interneurons. Studies in visual cortex indicate that synaptic connections between Pvalb+ cells are common while connections between Sst+ interneurons have not been observed. The inhibitory connectivity and kinetics of these two interneuron subpopulations, however, have not been characterized in medial entorhinal cortex (mEC). Using fluorescence-guided paired recordings in mouse brain slices from interneurons and excitatory cells in layer 2/3 mEC, we found that, unlike neocortical measures, Sst+ cells inhibit each other, albeit with a lower probability than Pvalb+ cells (18% vs 36% for unidirectional connections). Gap junction connections were also more frequent between Pvalb+ cells than between Sst+ cells. Pvalb+ cells inhibited each other with larger conductances, smaller decay time constants, and shorter delays. Similarly, synaptic connections between Pvalb+ and excitatory cells were more like...

In his editorial entitled “On Fallacies in Neuroscience,” Bernard (2020) takes his fellow neuroscientists to task for failures in logic that lead to the promulgation of fallacies and their entrenchment in the scientific literature. Drawing on his background in mathematics and philosophy, he highlights two common errors in logic that permeate our field. The first error he discusses leads to a fallacy known as “reverse inference.” The example he cites is subtle, but all the more telling because it “feels” correct before we are shown the problem. Imagine that my brain is in a scanner when I experience a bout of fear. The scan shows that a particular brain region (Bernard calls it Area Z) lights up brightly with the onset of my fear. One would be correct in proposing that Area Z is likely involved in my brain's processing of fear. The fallacious conclusion, however, would be to assert that if Area Z is lit, I must be experiencing fear. That is the “reverse” of the experimental design, which was to induce fear...

Regeneration can occur in peripheral neurons after injury, but the mechanisms involved are not fully delineated. Macrophages in dorsal root ganglia (DRGs) are involved in the enhanced regeneration that occurs after a conditioning lesion (CL), but how macrophages stimulate this response is not known. Oncomodulin (Ocm) has been proposed as a proregenerative molecule secreted by macrophages and neutrophils, is expressed in the DRG after axotomy, and stimulates neurite outgrowth by DRG neurons in culture. Wild-type (WT) and Ocm knock-out (KO) mice were used to investigate whether Ocm plays a role in the CL response in DRG neurons after sciatic nerve transection. Neurite outgrowth was measured after 24 and 48 h in explant culture 7 d after a CL. Sciatic nerve regeneration was also measured in vivo 7 d after a CL and 2 d after a subsequent sciatic nerve crush. The magnitude of the increased neurite outgrowth following a CL was significantly smaller in explants from Ocm KO mice than in explants from WT mice. In v...

G-protein-coupled receptors (GPCRs) coupled to Gi signaling, in particular downstream of monoaminergic neurotransmission, are posited to play a key role during developmental epochs (postnatal and juvenile) in shaping the emergence of adult anxiodepressive behaviors and sensorimotor gating. To address the role of Gi signaling in these developmental windows, we used a CaMKIIα-tTA::TRE hM4Di bigenic mouse line to express the hM4Di-DREADD (designer receptor exclusively activated by designer drugs) in forebrain excitatory neurons and enhanced Gi signaling via chronic administration of the DREADD agonist, clozapine- N -oxide (CNO) in the postnatal window (postnatal days 2–14) or the juvenile window (postnatal days 28–40). We confirmed that the expression of the HA-tagged hM4Di-DREADD was restricted to CaMKIIα-positive neurons in the forebrain, and that the administration of CNO in postnatal or juvenile windows evoked inhibition in forebrain circuits of the hippocampus and cortex, as indicated by a decline in exp...

Adult neural stem cells (NSCs) reside in two distinct niches in the mammalian brain, the ventricular-subventricular zone (V-SVZ) of the forebrain lateral ventricles and the subgranular zone (SGZ) of the hippocampal dentate gyrus. They are thought to be molecularly distinct since V-SVZ NSCs produce inhibitory olfactory bulb (OB) interneurons and SGZ NSCs excitatory dentate granule neurons. Here, we have asked whether this is so by directly comparing V-SVZ and SGZ NSCs from embryogenesis to adulthood using single-cell transcriptional data. We show that the embryonic radial glial precursor (RP) parents of these two NSC populations are very similar, but differentially express a small cohort of genes involved in glutamatergic versus GABAergic neurogenesis. These different RPs then undergo a similar gradual transition to a dormant adult NSC state over the first three postnatal weeks. This dormancy state involves transcriptional shutdown of genes that maintain an active, proliferative, prodifferentiation state an...

Protein hyperdeimination and deficiency of lyso-phospholipids (LPC 18:1) has been associated with the pathology of demyelinating disease in both humans and mice. We uncovered interesting biology of LPC 18:1, in which LPC 18:1 induced optic nerve function restoration through oligodendrocyte maturation and remyelination in mouse model systems. Our in vitro studies show LPC 18:1 protection against neuron-ectopic hyperdeimination and stimulation of oligodendrocyte maturation, while in vivo investigations recorded optic nerve function improvement following optic nerve injections of LPC 18:1, in contrast with LPC 18:0. Thus, just a change in a single bond renders a dramatic alternation in biological function. The incorporation of isobaric C13-histidine in newly synthesized myelin proteins and quantitative proteome shifts are consistent with remyelination underlying restoration in optic nerve function. These results suggest that exogenous LPC 18:1 may provide a therapeutic avenue for stemming vision loss in demye...