Faculty Bibliography

Background and Objectives: Maltreatment from the caregiver induces vulnerability to later life psychopathology. Animal models of early life stress suggest this is due to disruption of neural development of long-distance circuits linking amygdala to prefrontal cortex. Methods: We used a rat model of early life maltreatment to examine amygdala connectivity using resting-state functional magnetic resonance imaging (R-fMRI). Rat pups were reared by a mother provided with insufficient bedding for nest building or by one with abundant bedding from postnatal days (PND) 8 to 12. In adolescence (at PND 45) and in early adulthood (at PND 60), R-fMRI sessions were conducted under light (*1%) isofluorane anesthesia. Behavioral tests were obtained in animals reared under identical conditions to model negative affectivity, including the Forced Swim Test, Sucrose Preference Test, and Social Behavior Test. Results: Behaviors reflecting negative affectivity were seen in both adolescent and adult animals. Amygdala functional connectivity (FC) with frontal, parietal, and basal ganglia, including thalamus, increased significantly with increased age. By contrast, local amygdala FC decreased significantly with age. Additionally, we detected significant interactions between abuse condition and age. Local amygdala FC decreased between PND 45 and 60 in control rats, but increased significantly in abused rats. The reverse pattern was observed for amygdala FC with medial frontal cortex and parietal cortex. Conclusions: Translation of an in vivo longitudinal imaging approach to a rodent model of early caregiver maltreatment revealed enduring evidence of differences in brain functional connectivity in adulthood that likely underlies negative affectivity and vulnerability to internalizing psychopathology in humans

Background: Tau pathology is involved in multiple neurodegenerative disorders, for example in Alzheimer's disease, Parkinson's disease, and Frontotemporal dementia (FTD). Tau is a neuronal protein that binds microtubules and is thought to be involved in the stabilization of microtubules. Over 50 different mutations within the MAPT gene, the gene encoding for Tau, have been associated with inherited FTD. FTD is thought to involve deficits in the communication between neurons and in the mechanisms neuronal adaptation to experience, synaptic plasticity. The role of Tau in mechanisms of synaptic plasticity is not well-understood. To address this gap in the field, we have investigated synaptic plasticity and behavior in P301L mice, a mouse model for tau pathology that over-expresses human Tau protein carrying an inherited human mutation. Methods: Long-lasting forms of plasticity, late-phase long term potentiation (L-LTP) were examined in P301L (JNPL3) mice and age-matched controls by measuring field excitatory postsynaptic potentiation (fEPSP) in the CA1 hippocampal region after high frequency electrophysiological stimulation. Two behaviors associated with GABAergic function were assayed, prepulse inhibition of startle response (PPI) and susceptibility to epileptic seizures. GABAergic interneurons were stained using two markers; paravalbumin and somatostatin. Results: By examining long-lasting forms of plasticity in aged (>18 months old) in hippocampal brain slices we found surprisingly enhanced L-LTP in P301L mice compared to age-matched controls. The enhanced L-LTP in P301L slices was rescued by treatment with a GABA agonist, Zolpidem. These results suggest a loss of GABAergic neurons in P301L mice. Next we examined PPI and susceptibility to epileptic seizures in P301L and control mice. We found an altered PPI response and differences in epileptic seizures grades. Finally, we stained GABAergic interneurons in the hippocampus using two markers that identify GABAergic cell types showing a decrease in GABAergic neurons in the hippocampal CA1 region. Conclusions: Our results suggest that GABAergic interneurons are more vulnerable to molecular lesions caused by pathological Tau, which may result in the selective loss of hippocampal GABAergic interneurons. The molecular mechanisms involved in this specific GABAergic loss remains to be resolved, but may help to explain the pathophysiological symptoms of diseases like FTD, which involve altered Tau function

Integrated within neural circuits, astrocytes have recently been shown to modulate brain rhythms thought to mediate sleep function. Experimental evidence suggests that local impact of astrocytes on single synapses translates into global modulation of neuronal networks and behavior. We discuss these findings in the context of current conceptual models of sleep generation and function, each of which have historically focused on neural mechanisms. We highlight the implications and the challenges introduced by these results from a conceptual and computational perspective. We further provide modeling directions on how these data might extend our knowledge of astrocytic properties and sleep function. Given our evolving understanding of how local cellular activities during sleep lead to functional outcomes for the brain, further mechanistic and theoretical understanding of astrocytic contribution to these dynamics will undoubtedly be of great basic and translational benefit.

Background: Neurotrophin signaling of cholinergic basal forebrain (CBF) neurons is critical for survival and plasticity. Microaspiration of identified CBF neurons from postmortem human brain revealed a shift in balance of neurotrophin receptors toward cell death pathways during the progression of Alzheimer's disease (AD). Methods: In this study transcriptomic data from mouse basal forebrain cholinergic neurons (BFCNs; NCBI GEO GSE13379) were used to derive parameters for a deterministic kinetic model of the nerve growth factor (NGF) signaling pathway from Reactome, with TrkB receptor mechanisms added. This method is called Transcriptome-To-Reactome (TTR)-. The biosimulation was performed using COPASI software and included 11 compartments 435 species, and 263 reactions; 245 genes were used to determine initial values of species and kinetic values of reactions. The mouse BFCN model was considered baseline and a biosimulation was run with two doses of NGF, 500 m M and 10 mM, delivered as a bolus and for a 10 and 240 second duration, respectively. This approach tested selectively for p75 NTR and TrkA receptor mediated mechanisms. A second biosimulation test used a combination of 25 mM brain derived neurotrophic factor (BDNF) and 10 m M NGF as a continuous exposure for 60 min duration; this approach evaluated stimulation of p75 NTR TrkA, and TrkB. Based on the human microarray results demonstrating downregulation of TrkA (50%) and TrkB (60%), the corresponding parameters in the TTR biosimulation were decreased by the same amount. Results: Baseline results were validated from published literature on neuronal calcium levels mediated via the phospholipase C-g and inositol- 3-phosphate pathway at both bolus doses of NGF alone. With the corresponding parameters decreased in the TTR biosimulation, Figure 1: A) The reaction flux for c-RAF1 phosphorylation of MEK1 was delayed to peak value by 1.5 min from exposure, but the peak value was increased to 5 times the baseline value; B) Moreover, a slight shift t!

Background: Reductions in brain-derived neurotrophic factor (BDNF) have been implicated in the pathophysiology of Alzheimer's disease (AD). Nevertheless, the factors influencing central and peripheral BDNF levels are still poorly understood. Cerebral microvascular endothelial cells are known to be a major source of BDNF with a rate of production by far exceeding that of cortical neurons. Exposure of these cells to amyloid beta (Ab), results in cell death or injury with significant reductions in BDNF secretion. Moreover, in rodents, infusion of Ab40 into the carotid resulted in a disruption of endothelial cells, which was not observed with Ab42. Plasma Ab40 levels have also been associated with white matter hyperintense lesions (WMHI) on MRI scans in AD, an effect that may be mediated by the toxic effects of soluble Ab40 on small cerebral blood vessels and endothelial cells. Therefore, we hypothesized that concentrations of plasma Ab40, but not Ab42, would have a negative effect on plasma BDNF and on measures of white matter integrity as determined by Diffusion Tensor Imaging (DTI). Methods: To test this hypothesis, we examined BDNF and Ab levels in plasma from 119 subjects with intact cognition (no dementia and a Mini-Mental State Exam score of at least 28) and no gross MRI abnormalities other than white matter hyperintensities. Of these, 88 subjects also had BDNF in plasma determined. Results: Consistent with our prediction, Ab40 was inversely correlated with BDNF concentrations (P <.001), whereas Ab42 was independent (P = .231). Fractional anisotropy (FA; a measure of white matter integrity in DTI) was also inversely correlated with Ab40 (P = .001) and so was performance in delayed recall (P = .029). Conclusions: In cognitively intact individuals, circulating Ab40 results in reduction in plasma BDNF, white matter integrity (FA), and memory performance. As such, it may have prognostic significance

Functional neuronal homeostasis has been studied in a variety of model systems and contexts. Many studies have shown that there are a number of changes that can be activated within individual cells or networks in order to compensate for perturbations or changes in levels of activity. Dissociating the cell autonomous from the network-mediated events has been complicated due to the difficulty of sparsely targeting specific populations of neurons in vivo. Here, we make use of a recent in vivo approach we developed that allows for the sparse labeling and manipulation of activity within superficial caudal ganglionic eminence (CGE)-derived GABAergic interneurons. Expression of the inward rectifying potassium channel Kir2.1 cell-autonomously reduced neuronal activity and lead to specific developmental changes in their intrinsic electrophysiological properties and the synaptic input they received. In contrast to previous studies on homeostatic scaling of pyramidal cells, we did not detect any of the typically observed compensatory mechanisms in these interneurons. Rather, we instead saw a specific alteration of the kinetics of excitatory synaptic events within the reelin-expressing subpopulation of interneurons. These results provide the first in vivo observations for the capacity of interneurons to cell-autonomously regulate their excitability.