In Search of a Feedback Signal for Closed-Loop Deep Brain Stimulation: Stimulation of the Subthalamic Nucleus Reveals Altered Glutamate Dynamics in the Globus Pallidus in Anesthetized, 6-Hydroxydopamine-Treated Rats

Deep Brain Stimulation (DBS) of the subthalamic nucleus (STN) is a surgical procedure for alleviating motor symptoms of Parkinson’s Disease (PD). The pattern of DBS (e.g., the electrode pairs used and the intensity of stimulation) is usually optimized by trial and error based on a subjective evaluation of motor function. We tested the hypotheses that DBS releases glutamate in selected basal ganglia nuclei and that the creation of 6-hydroxydopamine (6-OHDA)-induced nigrostriatal lesions alters glutamate release during DBS in those basal ganglia nuclei. We studied the relationship between a pseudo-random binary sequence of DBS and glutamate levels in the STN itself or in the globus pallidus (GP) in anesthetized, control, and 6-OHDA-treated rats. We characterized the stimulus–response relationships between DBS and glutamate levels using a transfer function estimated using System Identification. Stimulation of the STN elevated glutamate levels in the GP and in the STN. Although the 6-OHDA treatment did not affect glutamate dynamics in the STN during DBS in the STN, the transfer function between DBS in the STN and glutamate levels in the GP was significantly altered by the presence or absence of 6-OHDA-induced lesions. Thus, glutamate responses in the GP in the 6-OHDA-treated animals (but not in the STN) depended on dopaminergic inputs. For this reason, measuring glutamate levels in the GP may provide a useful feedback target in a closed-loop DBS device in patients with PD since the dynamics of glutamate release in the GP during DBS seem to reflect the loss of dopaminergic neurons in the SNc

A Computer Model of Mammalian Central CO\u3csub\u3e2\u3c/sub\u3e Chemoreception

We developed a single compartment model of a mammalian CO2 sensitive neuron and tested the hypothesis that pH-dependent inhibition of multiple potassium channels contributes to CO2sensitivity. pH-dependent inhibition of potassium channels by either intracellular or extracellular pH was sufficient to alter neuronal activity, but changes in neither intracellular nor extracellular pH are required to elicit a neuronal response to hypercapnic stimulation

A Computer Model of Mammalian Central CO\u3csub\u3e2\u3c/sub\u3e Chemoreception

We developed a single compartment model of a mammalian CO2 sensitive neuron and tested the hypothesis that pH-dependent inhibition of multiple potassium channels contributes to CO2sensitivity. pH-dependent inhibition of potassium channels by either intracellular or extracellular pH was sufficient to alter neuronal activity, but changes in neither intracellular nor extracellular pH are required to elicit a neuronal response to hypercapnic stimulation

In Vivo Mapping of Cortical Columnar Networks in the Monkey with Focal Electrical and Optical Stimulation

There are currently largescale efforts underway to understand the brain as connection machine. However, there has been little emphasis on understanding connection patterns between functionally specific cortical columns. Here, we review development and application of focal electrical and optical stimulation methods combined with optical imaging and fMRI mapping in the nonhuman primate. These new approaches, when applied systematically on a large scale, will elucidate functionally specific intra-areal and inter-areal network connection patterns. Such functionally specific network data can provide accurate views of brain network topology

A Computational Analysis of Central CO2 Chemosensitivity in \u3ci\u3eHelix aspersa\u3c/i\u3e

We created a single-compartment computer model of a CO2 chemosensory neuron using differential equations adapted from the Hodgkin-Huxley model and measurements of currents in CO2 chemosensory neurons from Helix aspersa. We incorporated into the model two inward currents, a sodium current and a calcium current, three outward potassium currents, an A-type current (IKA), a delayed rectifier current (IKDR), a calcium-activated potassium current (IKCa), and a proton conductance found in invertebrate cells. All of the potassium channels were inhibited by reduced pH. We also included the pH regulatory process to mimic the effect of the sodium-hydrogen exchanger (NHE) described in these cells during hypercapnic stimulation. The model displayed chemosensory behavior (increased spike frequency during acid stimulation), and all three potassium channels participated in the chemosensory response and shaped the temporal characteristics of the response to acid stimulation. pH-dependent inhibition ofIKA initiated the response to CO2, but hypercapnic inhibition of IKDR and IKCaaffected the duration of the excitatory response to hypercapnia. The presence or absence of NHE activity altered the chemosensory response over time and demonstrated the inadvisability of effective intracellular pH (pHi) regulation in cells designed to act as chemostats for acid-base regulation. The results of the model indicate that multiple channels contribute to CO2 chemosensitivity, but the primary sensor is probably IKA. pHi may be a sufficient chemosensory stimulus, but it may not be a necessary stimulus: either pHi or extracellular pH can be an effective stimuli if chemosensory neurons express appropriate pH-sensitive channels. The lack of pHi regulation is a key feature determining the neuronal activity of chemosensory cells over time, and the balanced lack of pHi regulation during hypercapnia probably depends on intracellular activation of pHi regulation but extracellular inhibition of pHi regulation. These general principles are applicable to all CO2 chemosensory cells in vertebrate and invertebrate neurons

A Computational Analysis of Central CO2 Chemosensitivity in \u3ci\u3eHelix aspersa\u3c/i\u3e

We created a single-compartment computer model of a CO2 chemosensory neuron using differential equations adapted from the Hodgkin-Huxley model and measurements of currents in CO2 chemosensory neurons from Helix aspersa. We incorporated into the model two inward currents, a sodium current and a calcium current, three outward potassium currents, an A-type current (IKA), a delayed rectifier current (IKDR), a calcium-activated potassium current (IKCa), and a proton conductance found in invertebrate cells. All of the potassium channels were inhibited by reduced pH. We also included the pH regulatory process to mimic the effect of the sodium-hydrogen exchanger (NHE) described in these cells during hypercapnic stimulation. The model displayed chemosensory behavior (increased spike frequency during acid stimulation), and all three potassium channels participated in the chemosensory response and shaped the temporal characteristics of the response to acid stimulation. pH-dependent inhibition ofIKA initiated the response to CO2, but hypercapnic inhibition of IKDR and IKCaaffected the duration of the excitatory response to hypercapnia. The presence or absence of NHE activity altered the chemosensory response over time and demonstrated the inadvisability of effective intracellular pH (pHi) regulation in cells designed to act as chemostats for acid-base regulation. The results of the model indicate that multiple channels contribute to CO2 chemosensitivity, but the primary sensor is probably IKA. pHi may be a sufficient chemosensory stimulus, but it may not be a necessary stimulus: either pHi or extracellular pH can be an effective stimuli if chemosensory neurons express appropriate pH-sensitive channels. The lack of pHi regulation is a key feature determining the neuronal activity of chemosensory cells over time, and the balanced lack of pHi regulation during hypercapnia probably depends on intracellular activation of pHi regulation but extracellular inhibition of pHi regulation. These general principles are applicable to all CO2 chemosensory cells in vertebrate and invertebrate neurons

An Open Resource for Non-human Primate Optogenetics

© 2020 Elsevier Inc. Optogenetics has revolutionized neuroscience in small laboratory animals, but its effect on animal models more closely related to humans, such as non-human primates (NHPs), has been mixed. To make evidence-based decisions in primate optogenetics, the scientific community would benefit from a centralized database listing all attempts, successful and unsuccessful, of using optogenetics in the primate brain. We contacted members of the community to ask for their contributions to an open science initiative. As of this writing, 45 laboratories around the world contributed more than 1,000 injection experiments, including precise details regarding their methods and outcomes. Of those entries, more than half had not been published. The resource is free for everyone to consult and contribute to on the Open Science Framework website. Here we review some of the insights from this initial release of the database and discuss methodological considerations to improve the success of optogenetic experiments in NHPs