The adult brain continues to learn and can recover from injury, but the elements and operation of the neural circuits responsible for this plasticity are not known. In previous work we have: shown that locomotion dramatically enhances neural activity in the visual cortex (V1) of the mouse (Neill and Stryker, 2010); identified the cortical circuit responsible for this enhancement (Fu et al., 2014); and shown that locomotion also dramatically enhances adult plasticity (Kaneko and Stryker, 2014). The circuit responsible that is responsible for enhancing neural activity in the visual cortex contains both vasoactive intestinal peptide (VIP) and somatostatin (SST) neurons (Fu et al., 2014). Here we ask whether this VIP-SST circuit enhances plasticity directly, independent of locomotion and aerobic activity. Optogenetic activation or genetic blockade of this circuit reveal that it is both necessary and sufficient for rapidly increasing V1 cortical responses following manipulation of visual experience in adult mice. These findings reveal a disinhibitory circuit that regulates adult cortical plasticity.
Animal experimentation: Mice were maintained in the Laboratory Animal Research Center at University of California, San Francisco (UCSF) and used in accordance with protocol AN098080-02A-G approved by the UCSF Institutional Animal Care and Use Committee.
© 2015, Fu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Neurons generate and propagate electrical pulses called action potentials which annihilate on arrival at the axon terminal. We measure the extracellular electric field generated by propagating and annihilating action potentials and find that on annihilation, action potentials expel a local discharge. The discharge at the axon terminal generates an inhomogeneous electric field that immediately influences target neurons and thus provokes ephaptic coupling. Our measurements are quantitatively verified by a powerful analytical model which reveals excitation and inhibition in target neurons, depending on position and morphology of the source-target arrangement. Our model is in full agreement with experimental findings on ephaptic coupling at the well-studied Basket cell-Purkinje cell synapse. It is able to predict ephaptic coupling for any other synaptic geometry as illustrated by a few examples.
The classical diagnosis of Parkinsonism is based on motor symptoms that are the consequence of nigrostriatal pathway dysfunction and reduced dopaminergic output. However, a decade prior to the emergence of motor issues, patients frequently experience non-motor symptoms, such as a reduced sense of smell (hyposmia). The cellular and molecular bases for these early defects remain enigmatic. To explore this, we developed a new collection of five fruit fly models of familial Parkinsonism and conducted single-cell RNA sequencing on young brains of these models. Interestingly, cholinergic projection neurons are the most vulnerable cells, and genes associated with presynaptic function are the most deregulated. Additional single nucleus sequencing of three specific brain regions of Parkinson’s disease patients confirms these findings. Indeed, the disturbances lead to early synaptic dysfunction, notably affecting cholinergic olfactory projection neurons crucial for olfactory function in flies. Correcting these defects specifically in olfactory cholinergic interneurons in flies or inducing cholinergic signaling in Parkinson mutant human induced dopaminergic neurons in vitro using nicotine, both rescue age-dependent dopaminergic neuron decline. Hence, our research uncovers that one of the earliest indicators of disease in five different models of familial Parkinsonism is synaptic dysfunction in higher-order cholinergic projection neurons and this contributes to the development of hyposmia. Furthermore, the shared pathways of synaptic failure in these cholinergic neurons ultimately contribute to dopaminergic dysfunction later in life.