Inhibition has long been thought to stabilize the activity of cortical networks at low rates, and to shape significantly their response to sensory inputs. In this talk, I will describe three recent collaborative projects that shed light on these issues. (1) I will show how optogenetic excitation of inhibition neurons is consistent with cortex being inhibition stabilized even in the absence of sensory inputs, and how this data can constrain the coupling strengths of E-I cortical network models. (2) Recent analysis of the effects of optogenetic excitation of pyramidal cells in V1 of mice and monkeys shows that in some cases this optogenetic input reshuffles the firing rates of neurons of the network, leaving the distribution of rates unaffected. I will show how this surprising effect can be reproduced in sufficiently strongly coupled E-I networks. (3) Another puzzle has been to understand the respective roles of different inhibitory subtypes in network stabilization. Recent data reveal a novel, state dependent, paradoxical effect of weakening AMPAR mediated synaptic currents onto SST cells. Mathematical analysis of a network model with multiple inhibitory cell types shows that this effect tells us in which conditions SST cells are required for network stabilization.

A key issue in understanding circuit operations is the extent to which neuronal spiking reflects local computation or responses to upstream inputs. Several studies have lesioned or silenced inputs to area CA1 of the hippocampus - either area CA3 or the entorhinal cortex and examined the effect on CA1 pyramidal cells. However, the types of the reported physiological impairments vary widely, primarily because simultaneous manipulations of these redundant inputs have never been performed. In this study, I combined optogenetic silencing of unilateral and bilateral mEC, of the local CA1 region, and performed bilateral pharmacogenetic silencing of CA3. I combined this with high spatial resolution extracellular recordings along the CA1-dentate axis. Silencing the medial entorhinal largely abolished extracellular theta and gamma currents in CA1, without affecting firing rates. In contrast, CA3 and local CA1 silencing strongly decreased firing of CA1 neurons without affecting theta currents. Each perturbation reconfigured the CA1 spatial map. Yet, the ability of the CA1 circuit to support place field activity persisted, maintaining the same fraction of spatially tuned place fields. In contrast to these results, unilateral mEC manipulations that were ineffective in impacting place cells during awake behavior were found to alter sharp-wave ripple sequences activated during sleep. Thus, intrinsic excitatory-inhibitory circuits within CA1 can generate neuronal assemblies in the absence of external inputs, although external synaptic inputs are critical to reconfigure (remap) neuronal assemblies in a brain-state dependent manner.

How inclusive and diverse is non-invasive brain stimulation in the treatment of psychiatric disorders?Indira Tendolkar, Donders Institute for Brain, Cognition and Behavior, Department of Psychiatry. Mental illness is associated with a huge socioeconomic burden worldwide, with annual costs only in the Netherlands of €22 billion. Over two decades of cognitive and affective neuroscience research with modern tools of neuroimaging and neurophysiology in humans have given us a wealth of information about neural circuits underlying the main symptom domains of psychiatric disorders and their remediation. Neuromodulation entails the alteration of these neural circuits through invasive (e.g., DBS) or non-invasive (e.g., TMS) techniques with the aim of improving symptoms and/or functions and enhancing neuroplasticity. In my talk, I will focus on neuromodulation studies using repetitive transcranial magnetic stimulation (rTMS) as a relatively safe, noninvasive method, which can be performed simultaneously with neurocognitive interventions. Using the examples of two chronifying mental illnesses, namely obsessive compulsive disorders and major depressive disorder (MDD), I will review the concept of "state dependent" effects of rTMS and highlight how simultaneous or sequential cognitive interventions could help optimize rTMS therapy by providing further control of ongoing neural activity in targeted neural networks. Hardly any attention has been paid to diversity aspects in the studies. By including studies from low- and middle income countries, I will discuss the potential of non-invasive brain stimulation from a transcultural perspective.