Activation of Somatostatin Interneurons by Nicotinic Modulator Lypd6 Enhances Plasticity and Functional Recovery in the Adult Mouse Visual Cortex

Abstract

The limitation of plasticity in the adult brain impedes functional recovery later in life from brain injury or disease. This pressing clinical issue may be resolved by enhancing plasticity in the adult brain. One strategy for triggering robust plasticity in adulthood is to reproduce one of the hallmark physiological events of experience-dependent plasticity observed during the juvenile critical period: to rapidly reduce the activity of parvalbumin (PV)-expressing interneurons and disinhibit local excitatory neurons. This may be achieved through the enhancement of local inhibitory inputs, particularly those of somatostatin (SST)-expressing interneurons. However, to date the means for manipulating SST interneurons for enhancing cortical plasticity in the adult brain are not known. We show that SST interneuron-selective overexpression of Lypd6, an endogenous nicotinic signaling modulator, enhances ocular dominance plasticity in the adult primary visual cortex (V1). Lypd6 overexpression mediates a rapid experiencedependent increase in the visually evoked activity of SST interneurons as well as a simultaneous reduction in PV interneuron activity and disinhibition of excitatory neurons. Recapitulating this transient activation of SST interneurons using chemogenetics similarly enhanced V1 plasticity. Notably, we show that SST-selective Lypd6 overexpression restores visual acuity in amblyopic mice that underwent early long-term monocular deprivation. Our data in both male and female mice reveal selective modulation of SST interneurons and a putative downstream circuit mechanism as an effective method for enhancing experience-dependent cortical plasticity as well as functional recovery in adulthood.

Adolescent frontal top-down neurons receive heightened local drive to establish adult attentional behavior in mice

“…Preparatory surgery leading to, and recording itself was performed initially under Nembutal/chlorprothixene anesthesia and then maintained with isoflurane 64 . Optogenetically tagged ACAvis neurons were identified using a laser (wavelength 473 nm, 1ms duration, 5 Hz) search stimulus emitted and delivered through the optic fiber (diameter 105 μm) coupled with a linear sixteen-channel silicon probes with 177 μm 2 recording sites (NeuroNexus Technologies, Ann Arbor, MI) spaced 50 μm apart and oriented immediately above the ACA cortical surface.…”

Nicotinic regulation of local and long-range input balance drives top-down attentional circuit maturation

“…Lynx1 was amplified from a cDNA library derived from mouse cortex and subcloned into a pcDNA3.1(−) vector for an overexpression vector. For Lynx1 KD vector, following procedures previously described in ( 68 ), we used short hairpin RNA (shRNA) vector with limited reported off-target effects, in which shRNA is embedded into a larger endogenous microRNA loop that allows robust expression from RNA polymerase 2 promoters of an AAV vector to avoid the recently reported potential off-target effect by the use of acute short hairpin–based KD. Two oligonucleotides including shRNA sequence for Lynx1 were subcloned into pcDNA6.2-GW/ EmGfp -miR using BLOCK-iT Pol II miR RNAi Expression Vector Kit with EmGFP (Life Technologies).…”

Adolescent frontal top-down neurons receive heightened local drive to establish adult attentional behavior in mice

“…In vivo extracellular electrophysiology. Preparatory surgery leading to, and recording itself was performed initially under Nembutal/chlorprothixene anesthesia and then maintained with isoflurane 64 . Optogenetically tagged ACAvis neurons were identified using a laser (wavelength 473 nm, 1 ms duration, 5 Hz) search stimulus emitted and delivered through the optic fiber (diameter 105 μm) coupled with a linear sixteen-channel silicon probes with 177 μm 2 recording sites (NeuroNexus Technologies, Ann Arbor, MI) spaced 50 μm apart and oriented immediately above the ACA cortical surface.…”

“…To ensure single-unit isolation, the waveforms of recorded units were further examined using Offline Sorter (Plexon). To analyze the electrophysiology data, firing rate was computed during 3 min laser off session mentioned above by a MATLAB R2018b (MathWorks) script established in a published study 64 . Only sorted units whose spike width time (trough-to-peak time) is more than 400 μs were included in the analysis, and were further separated to optgenetically tagged ChR2 (+) ACAvis neurons if they showed time-locked spiking response within 2 ms upon laser pulse stimulation, and ChR2 (−) ACA neurons for the rest of units.…”