Biology subjects

Wise, D. L.

Publications and source records attributed to Wise, D. L..

3 recordsLinked to original sources

bioRxiv2023

Progressive circuit hyperexcitability in mouse neocortical slice cultures with increasing duration of activity silencing

Forebrain neurons deprived of activity become hyperactive when activity is restored. Rebound activity has been linked to spontaneous seizures in vivo following prolonged activity blockade. Here we measured the time course of rebound activity and the contributing circuit mechanisms using calcium imaging, synaptic staining and whole cell patch clamp in organotypic slice cultures of mouse neocortex. Calcium imaging revealed hypersynchronous activity increasing in intensity with longer periods of deprivation. While activity partially recovered three days after slices were released from five days of deprivation, they were less able to recover after ten days of deprivation. However, even after the longer period of deprivation, activity patterns eventually returned to baseline levels. The degree of deprivation-induced rebound was age-dependent, with the greatest effects occurring when silencing began in the second week. Pharmacological blockade of NMDA receptors indicated that hypersynchronous rebound activity did not require Hebbian plasticity evoked. In single neuron recordings, input resistance roughly doubled with a concomitant increase in intrinsic excitability. Synaptic imaging of pre- and postsynaptic proteins revealed dramatic reductions in the number of presumptive synapses with a larger effect on inhibitory than seen in excitatory synapses. Putative excitatory synapses colocalizing PSD-95 and Bassoon declined by 39% and 56% following five and ten days of deprivation, but presumptive inhibitory synapses colocalizing gephyrin and VGAT declined by 55% and 73% respectively. The results suggest that with prolonged deprivation, a progressive reduction in synapse number is accompanied by a shift in the balance between excitation and inhibition and increased cellular excitability. SIGNIFICANCE STATEMENTWhen cortical activity is silenced during development, lifelong seizures often result. Here we explored whether these seizures result from overcompensation of homeostatic recovery mechanisms. Prior work showed that neurons briefly deprived of the ability to fire action potentials compensate by becoming more excitable, increasing synaptic drive and intrinsic excitability. We found that prolonged silencing of cortex produced a profound loss of synapse density, especially for inhibitory synapses, pointing to a circuit unable to maintain excitatory/inhibitory balance. These results show that homeostatic responses, which are normally restorative, can result in maladaptive circuit configurations when brought to extremes.

neuroscience↗

bioRxiv2021

A transcriptional constraint mechanism limits the homeostatic response to activity deprivation in mammalian neocortex

Healthy neuronal networks rely on homeostatic plasticity to maintain stable firing rates despite changing synaptic drive. These mechanisms, however, can themselves be destabilizing if activated inappropriately or excessively. For example, prolonged activity deprivation can lead to rebound hyperactivity and seizures. While many forms of homeostasis have been described, whether and how the magnitude of homeostatic plasticity is constrained remains unknown. Here we uncover negative regulation of cortical network homeostasis by the PARbZIP family of transcription factors. In cortical slice cultures made from knockout mice lacking all three of these factors, the network response to prolonged activity withdrawal measured with calcium imaging is much stronger, while baseline activity is unchanged. Whole cell recordings reveal an exaggerated increase in the frequency of miniature excitatory synaptic currents reflecting enhanced upregulation of recurrent excitatory synaptic transmission. Genetic analyses reveal that two of the factors, Hlf and Tef, are critical for constraining plasticity and for preventing life-threatening seizures. These data indicate that transcriptional activation is not only required for many forms of homeostatic plasticity but is also involved in restraint of the response to activity deprivation.

neuroscience↗

bioRxiv2017

Development of cross-orientation suppression and size tuning and the role of experience

Many sensory neural circuits exhibit response normalization, which occurs when the response of a neuron to a combination of multiple stimuli is less than the sum of the responses to the individual stimuli presented alone. In the visual cortex, normalization takes the forms of cross-orientation suppression and surround suppression. At the onset of visual experience, visual circuits are partially developed and exhibit some mature features such as orientation selectivity, but it is unknown whether cross-orientation suppression or surround suppression are present at the onset of visual experience or require visual experience for their emergence. We characterized the development of these properties and their dependence on visual experience in ferrets. Visual experience was varied across three conditions: typical rearing, dark rearing, and dark rearing with daily exposure to simple sinusoidal gratings (14-16 hours total). Cross-orientation suppression and surround suppression were noted in the earliest observations, and did not vary considerably with experience. We also observed evidence of continued maturation of receptive field properties in the second month of visual experience: substantial length summation was observed only in the oldest animals (postnatal day 90); evoked firing rates were greatly increased in older animals; and direction selectivity required experience, but declined slightly in older animals. These results constrain the space of possible circuit implementations of these features.\n\nSignificance StatementThe development of the brain depends on both nature - factors that are independent of the experience of an individual animal - and nurture - factors that depend on experience. While orientation selectivity, one of the major response properties of neurons in visual cortex, is already present at the onset of visual experience, it is unknown if response properties that depend on interactions among multiple stimuli develop without experience. We find that the properties of crossorientation suppression and surround suppression are present at eye opening, and do not depend on visual experience. Our results are consistent with the idea that a majority of the basic properties of sensory neurons in primary visual cortex are derived independent of the experience of an individual animal.

neuroscience↗