Biology subjects

Stephen David Shea

Publications and source records attributed to Stephen David Shea.

3 recordsLinked to original sources

bioRxiv2016

MECP2 regulates cortical plasticity underlying a learned behavior in adult female mice

Neurodevelopmental disorders begin with the emergence of inappropriate synaptic connectivity early in life, yet how the sustained disruption of experience-dependent plasticity aggravates symptoms in adulthood is unclear. Here we used pup retrieval learning to assay adult cortical plasticity in a female mouse model of Rett syndrome (MeCP2het). We show that auditory cortical plasticity and retrieval learning are impaired in MeCP2het. Specifically, normal MECP2 expression in the adult auditory cortex is required for efficient retrieval learning. In wild-type mice, cohabitation with a mother and her pups triggered transient changes to auditory cortical inhibitory networks, including elevated levels of the GABA-synthesizing enzyme GAD67. However, MeCP2het further exhibited increased expression of parvalbumin (PV) and perineuronal nets (PNNs), events thought to suppress plasticity at the closure of critical periods and in adult learning. Averting these events with genetic and pharmacological manipulations of the GABAergic network restored retrieval behavior. We propose that adult retrieval learning triggers a transient episode of inhibitory plasticity in the auditory cortex that is dysregulated in MeCP2het. This window of heightened sensitivity to social sensory cues reveals a role of MeCP2 mutations in facilitating adult plasticity that is distinct from their effects on early development.

Neuroscience↗

bioRxiv2014

Noradrenergic plasticity of olfactory sensory neuron inputs to the main olfactory bulb

Sensory responses are modulated throughout the nervous system by internal factors including attention, experience, and brain state. This is partly due to fluctuations in neuromodulatory input from regions such as the noradrenergic locus coeruleus (LC) in the brainstem. LC activity changes with arousal and modulates sensory processing, cognition and memory. The main olfactory bulb (MOB) is richly targeted by LC fibers and noradrenaline profoundly influences MOB circuitry and odor-guided behavior. Noradrenaline-dependent plasticity affects the output of the MOB. However, it is unclear whether noradrenergic plasticity includes modulation in the glomerular layer, the site of input to the MOB. Noradrenergic terminals are found in the glomerular layer, but noradrenaline receptor activation does not seem to acutely modulate olfactory sensory neuron terminals in vitro. We investigated whether noradrenaline induces plasticity at the glomerulus. We used wide-field optical imaging to measure changes in odor responses following electrical stimulation of locus coeruleus in anesthetized mice. Surprisingly, the odor-evoked intrinsic optical signals at the glomerulus were persistently weakened after LC activation. Calcium imaging selectively from olfactory sensory neurons confirmed that this effect was due to a uniform gain suppression of presynaptic input, and did not require exposure to a stimulus during the LC activation. Finally, noradrenaline antagonists prevented glomerular suppression. We conclude that noradrenaline release from LC has persistent effects on odor processing already at the first synapse of the main olfactory system. This mechanism could contribute to arousal-dependent memories.

Neuroscience↗

bioRxiv2014

Broadly tuned and respiration-independent inhibition in the olfactory bulb of awake mice

Olfactory representations are shaped by both brain state and respiration; however, the interaction and circuit substrates of these influences are poorly understood. Granule cells (GCs) in the main olfactory bulb (MOB) are presumed to sculpt activity that reaches the olfactory cortex via inhibition of mitral/tufted cells (MTs). GCs may potentially sparsen ensemble activity by facilitating lateral inhibition among MTs, and/or they may enforce temporally-precise activity locked to breathing. Yet, the selectivity and temporal structure of GC activity during wakefulness are unknown. We recorded GCs in the MOB of anesthetized and awake mice and reveal pronounced state-dependent features of odor coding and temporal patterning. Under anesthesia, GCs exhibit sparse activity and are strongly and synchronously coupled to the respiratory cycle. Upon waking, GCs desynchronize, broaden their odor responses, and typically fire without regard for the respiratory rhythm. Thus during wakefulness, GCs exhibit stronger odor responses with less temporal structure. Based on these observations, we propose that during wakefulness GCs likely predominantly shape MT odor responses through broadened lateral interactions rather than respiratory synchronization.

Neuroscience↗