Faculty Bibliography

The central nervous system is plastic throughout life, but is most sensitive to the statistics of the sensory environment during critical periods of early postnatal development. In the auditory cortex, various forms of acoustic experience have been found to shape the formation of receptive fields and influence the overall rate of cortical organization. The synaptic mechanisms that control cortical receptive field plasticity are beginning to be described, particularly for frequency tuning in rodent primary auditory cortex. Inhibitory circuitry plays a major role in critical period regulation, and new evidence suggests that the formation of excitatory-inhibitory balance determines the duration of critical period plasticity for auditory cortical frequency tuning. Cortical inhibition is poorly tuned in the infant brain, but becomes co-tuned with excitation in an experience-dependent manner over the first postnatal month. We discuss evidence suggesting that this may be a general feature of the developing cortex, and describe the functional implications of such transient excitatory-inhibitory imbalance

Despite the growing public interest in perfluorinated compounds (PFCs), very few studies have reported the sources and pathways of human exposure to these compounds in China. In this study, concentrations of 10 PFCs were measured in human blood, water (tap water and surface water), freshwater fish, and seafood samples collected from China. On the basis of the data, we calculated daily intakes of PFCs, regional differences in human exposures, and potential risks associated with ingestion of PFCs from diet, drinking water, and indoor dust for the Chinese population. Perfluorooctane sulfonate (PFOS) was the most predominant PFC found with a mean concentration of 12.5 ng/mL in human blood from Tianjin and 0.92 ng/g wet wt in freshwater fish and seafood; perfluorooctanoic acid (PFOA) was the major PFC found in drinking water at a concentration range of 0.10 to 0.92 ng/L. The estimated daily intake of PFOS and PFOA via fish and seafood consumption (EDI(fish&seafood)) ranged from 0.10 to 2.51 and 0.13 to 0.38 ng/kg bw/day, respectively, for different age groups (i.e., toddlers, adolescents and children, and adults) from selected locations (i.e., Tianjin, Nanchang, Wuhan, and Shenyang). The EDI(fish&seafood) of PFCs decreased (p < 0.05) with age. The estimated daily intake of PFOS and PFOA via drinking water consumption (EDI(drinking water)) ranged from 0.006 to 0.014 and 0.010 to 0.159 ng/kg bw/day, respectively. Comparison of EDI(fish&seafood) and EDI(drinking water) values with those of the modeled total dietary intake (TDI) of PFCs by adults from Tianjin, Nanchang, Wuhan, and Shenyang showed that contributions of fish and seafood to TDI of PFOS varied depending on the location. Fish and seafood accounted for 7%, 24%, 80%, and 84% of PFOS intake in Nanchang, Shenyang, Wuhan, and Tianjin, respectively, suggesting regional differences in human exposure to PFOS. Drinking water was a minor source of PFOS (<1%) exposure in adults from all the study locations.

Recent morphological and physiological studies have suggested a strong relationship between the suprageniculate nucleus (Sg) of the posterior thalamus and the input structure of the basal ganglia, the caudate nucleus (CN) of the feline brain. Accordingly, to clarify if there is a real functional relationship between Sg and CN during visual information processing, we investigated the temporal relations of simultaneously recorded neuronal spike trains of these two structures, looking for any significant cross-correlation between the spiking of the simultaneously recorded neurons. For the purposes of statistical analysis, we used the shuffle and jittering resampling methods. Of the recorded 288 Sg-CN neuron pairs, 26 (9.2%) showed significantly correlated spontaneous activity. Nineteen pairs (6.7%) showed correlated activity during stationary visual stimulation, while 21 (7.4%) pairs during stimulus movement. There was no overlap between the neuron pairs that showed cross-correlated spontaneous activity and the pairs that synchronized their activity during visual stimulation. Thus visual stimulation seems to have been able to synchronize, and also, by other neuron pairs, desynchronize the activity of CN and Sg. In about half of the cases, the activation of Sg preceded the activation of CN by a few milliseconds, while in the other half, CN was activated earlier. Our results provide the first piece of evidence for the existence of a functional cooperation between Sg and CN. We argue that either a monosynaptic bidirectional direct connection should exist between these structures, or a common input comprising of parallel pathways synchronizing them.

alpha-dystroglycan is a highly O-glycosylated extracellular matrix receptor that is required for anchoring of the basement membrane to the cell surface and for the entry of Old World arenaviruses into cells. Like-acetylglucosaminyltransferase (LARGE) is a key molecule that binds to the N-terminal domain of alpha-dystroglycan and attaches ligand-binding moieties to phosphorylated O-mannose on alpha-dystroglycan. Here we show that the LARGE modification required for laminin- and virus-binding occurs on specific Thr residues located at the extreme N terminus of the mucin-like domain of alpha-dystroglycan. Deletion and mutation analyses demonstrate that the ligand-binding activity of alpha-dystroglycan is conferred primarily by LARGE modification at Thr-317 and -319, within the highly conserved first 18 amino acids of the mucin-like domain. The importance of these paired residues in laminin-binding and clustering activity on myoblasts and in arenavirus cell entry is confirmed by mutational analysis with full-length dystroglycan. We further demonstrate that a sequence of five amino acids, Thr(317)ProThr(319)ProVal, contains phosphorylated O-glycosylation and, when modified by LARGE is sufficient for laminin-binding. Because the N-terminal region adjacent to the paired Thr residues is removed during posttranslational maturation of dystroglycan, our results demonstrate that the ligand-binding activity resides at the extreme N terminus of mature alpha-dystroglycan and is crucial for alpha-dystroglycan to coordinate the assembly of extracellular matrix proteins and to bind arenaviruses on the cell surface

The ability of human subjects to choose between disparate kinds of rewards suggests that the neural circuits for valuing different reward types must converge. Economic theory suggests that these convergence points represent the subjective values (SVs) of different reward types on a common scale for comparison. To examine these hypotheses and to map the neural circuits for reward valuation we had food and water-deprived subjects make risky choices for money, food, and water both in and out of a brain scanner. We found that risk preferences across reward types were highly correlated; the level of risk aversion an individual showed when choosing among monetary lotteries predicted their risk aversion toward food and water. We also found that partially distinct neural networks represent the SVs of monetary and food rewards and that these distinct networks showed specific convergence points. The hypothalamic region mainly represented the SV for food, and the posterior cingulate cortex mainly represented the SV for money. In both the ventromedial prefrontal cortex (vmPFC) and striatum there was a common area representing the SV of both reward types, but only the vmPFC significantly represented the SVs of money and food on a common scale appropriate for choice in our data set. A correlation analysis demonstrated interactions across money and food valuation areas and the common areas in the vmPFC and striatum. This may suggest that partially distinct valuation networks for different reward types converge on a unified valuation network, which enables a direct comparison between different reward types and hence guides valuation and choice.

Cerebellar output is necessary for the ideal implementation of many nervous system functions, particularly motor coordination. A key step toward understanding the generation of this output is characterizing the factors that shape the activity of the cerebellar nuclei (CN). There are four major sources of synaptic input that modulate CN activity; collaterals of climbing and mossy fibers are two, and the remaining two are provided by Purkinje cell (PC) axons in the form of simple spikes (SSs) and complex spikes (CSs). Most hypotheses of cerebellar function focus on SSs as the primary determinant of CN activity. However, it is likely that CSs also cause significant direct effects on CN activity, something that is rarely considered. To explore this possibility, we recorded from synaptically connected PC-CN neuron cell pairs in rats. Cross-correlograms of CS and CN activity from such recordings demonstrate that spontaneous CSs have a strong inhibitory effect on CN activity, apparently sufficient, in some cases, to trigger changes in the intrinsic excitability of the CN neuron that long outlast the underlying CS-mediated GABAergic IPSP. Furthermore, many CS-CN correlograms show an initial excitatory response, demonstrating the ability of climbing fiber collaterals to significantly excite CN neurons. A substantial fraction (24%) of correlograms displayed an excitation-inhibition sequence, providing evidence that a CN neuron often receives collaterals from the same olivocerebellar axons as innervate the PCs projecting to it. Thus, excitation followed by inhibition appears to be a hard-wired response pattern of many CN neurons to olivocerebellar activity

Background: Autism has been hypothesized to reflect neuronal disconnection. Several recent reports implicate the key thalamic relay nuclei and cortico-thalamic connectivity in the pathophysiology of autism. Accordingly, we aimed to focus on evaluating the integrity of the thalamic radiation and sought to replicate prior white matter findings in Korean boys with high-functioning autism spectrum disorders (ASD) using Diffusion Tensor Imaging (DTI). Methods: We compared fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) in 17 boys with ASD and 17 typically developing controls in the anterior thalamic radiation (ATR), superior thalamic radiation (STR), posterior thalamic radiation (PTR), corpus callosum (CC), uncinate fasciculus (UF) and inferior longitudinal fasciculus (ILF). Results: The two groups were group-matched on age, IQ, handedness and head circumference. In whole-brain voxel-wise analyses, FA was significantly reduced and MD was significantly increased in the right ATR, CC, and left UF in subjects with ASD (p<0.05, corrected). We found significantly lower FA in right and left ATR, CC, left UF and right and left ILF and significantly higher MD values of the CC in the ASD group in region of interest-based analyses. We also observed significantly higher RD values of right and left ATR, CC, left UF, left ILF in subjects with ASD compared to typically developing boys and significantly lower AD values of both ILF. Right ATR and right UF FA was significantly negatively correlated with total SRS score within the ASD group (r=-.56, p=.02). Conclusions: Our preliminary findings support evidence implicating disturbances in the thalamo-frontal connections in autism. These findings highlight the role of hypoconnectivity between the frontal cortex and thalamus in ASD

Short-term synaptic plasticity (STP) is widely thought to play an important role in information processing. This major function of STP has recently been challenged, however, by several computational studies indicating that transmission of information by dynamic synapses is broadband, i.e., frequency independent. Here we developed an analytical approach to quantify time- and rate-dependent synaptic information transfer during arbitrary spike trains using a realistic model of synaptic dynamics in excitatory hippocampal synapses. We found that STP indeed increases information transfer in a wide range of input rates, which corresponds well to the naturally occurring spike frequencies at these synapses. This increased information transfer is observed both during Poisson-distributed spike trains with a constant rate and during naturalistic spike trains recorded in hippocampal place cells in exploring rodents. Interestingly, we found that the presence of STP in low release probability excitatory synapses leads to optimization of information transfer specifically for short high-frequency bursts, which are indeed commonly observed in many excitatory hippocampal neurons. In contrast, more reliable high release probability synapses that express dominant short-term depression are predicted to have optimal information transmission for single spikes rather than bursts. This prediction is verified in analyses of experimental recordings from high release probability inhibitory synapses in mouse hippocampal slices and fits well with the observation that inhibitory hippocampal interneurons do not commonly fire spike bursts. We conclude that STP indeed contributes significantly to synaptic information transfer and may serve to maximize information transfer for specific firing patterns of the corresponding neurons.

Olfactory systems encode odours by which neurons respond and by when they respond. In mammals, every sniff evokes a precise, odour-specific sequence of activity across olfactory neurons. Likewise, in a variety of neural systems, ranging from sensory periphery to cognitive centres, neuronal activity is timed relative to sampling behaviour and/or internally generated oscillations. As in these neural systems, relative timing of activity may represent information in the olfactory system. However, there is no evidence that mammalian olfactory systems read such cues. To test whether mice perceive the timing of olfactory activation relative to the sniff cycle ('sniff phase'), we used optogenetics in gene-targeted mice to generate spatially constant, temporally controllable olfactory input. Here we show that mice can behaviourally report the sniff phase of optogenetically driven activation of olfactory sensory neurons. Furthermore, mice can discriminate between light-evoked inputs that are shifted in the sniff cycle by as little as 10 milliseconds, which is similar to the temporal precision of olfactory bulb odour responses. Electrophysiological recordings in the olfactory bulb of awake mice show that individual cells encode the timing of photoactivation in relation to the sniff in both the timing and the amplitude of their responses. Our work provides evidence that the mammalian olfactory system can read temporal patterns, and suggests that timing of activity relative to sampling behaviour is a potent cue that may enable accurate olfactory percepts to form quickly.

During light slow-wave sleep, the thalamo-cortical network oscillates in waxing-and-waning patterns at about 7 to 14 Hz and lasting for 500 ms to 3 s, called spindles, with the thalamus rhythmically sending strong excitatory volleys to the cortex. Concurrently, the hippocampal activity is characterized by transient and strong excitatory events, Sharp-Waves-Ripples (SPWRs), directly affecting neocortical activity--in particular the medial prefrontal cortex (mPFC)--which receives monosynaptic fibers from the ventral hippocampus and subiculum. Both spindles and SPWRs have been shown to be strongly involved in memory consolidation. However, the dynamics of the cortical network during natural sleep spindles and how prefrontal circuits simultaneously process hippocampal and thalamo-cortical activity remain largely undetermined. Using multisite neuronal recordings in rat mPFC, we show that during sleep spindles, oscillatory responses of cortical cells are different for different cell types and cortical layers. Superficial neurons are more phase-locked and tonically recruited during spindle episodes. Moreover, in a given layer, interneurons were always more modulated than pyramidal cells, both in firing rate and phase, suggesting that the dynamics are dominated by inhibition. In the deep layers, where most of the hippocampal fibers make contacts, pyramidal cells respond phasically to SPWRs, but not during spindles. Similar observations were obtained when analyzing gamma-oscillation modulation in the mPFC. These results demonstrate that during sleep spindles, the cortex is functionnaly "deafferented" from its hippocampal inputs, based on processes of cortical origin, and presumably mediated by the strong recruitment of inhibitory interneurons. The interplay between hippocampal and thalamic inputs may underlie a global mechanism involved in the consolidation of recently formed memory traces.