Distinct local and brain-wide networks are activated by optogenetic stimulation of neurons specific to each layer of motor cortex.

Primary motor cortex (M1) consists of a stack of interconnected but distinct layers (L1-L6) which affect motor control through large-scale networks. However, the brain-wide functional influence of each layer is poorly understood. We sought to expand our knowledge of these layers' circuitry by combining Cre-driver mouse lines, optogenetics, fMRI, and electrophysiology. Neuronal activities initiated in Drd3 neurons (within L2/3) were mainly confined within M1, while stimulation of Scnn1a, Rbp4, and Ntsr1 neurons (within L4, L5, and L6, respectively) evoked distinct responses in M1 and motor-related subcortical regions, including striatum and motor thalamus. We also found that fMRI responses from targeted stimulations correlated with both local field potentials (LFPs) and spike changes. This study represents a step forward in our understanding of how different layers of primary motor cortex are embedded in brain-wide circuitry.

Repeated hippocampal seizures lead to brain-wide reorganization of circuits and seizure propagation pathways.

Repeated seizure activity can lead to long-term changes in seizure dynamics and behavior. However, resulting changes in brain-wide dynamics remain poorly understood. This is due partly to technical challenges in precise seizure control and in vivo whole-brain mapping of circuit dynamics. Here, we developed an optogenetic kindling model through repeated stimulation of ventral hippocampal CaMKII neurons in adult rats. We then combined fMRI with electrophysiology to track brain-wide circuit dynamics resulting from non-afterdischarge (AD)-generating stimulations and individual convulsive seizures. Kindling induced widespread increases in non-AD-generating stimulation response and ipsilateral functional connectivity and elevated anxiety. Individual seizures in kindled animals showed more significant increases in brain-wide activity and bilateral functional connectivity. Onset time quantification provided evidence for kindled seizure propagation from the ipsilateral to the contralateral hemisphere. Furthermore, a core of slow-migrating hippocampal activity was identified in both non-kindled and kindled seizures, revealing a novel mechanism of seizure sustainment and propagation.

High-sensitivity detection of optogenetically-induced neural activity with functional ultrasound imaging.

Whole-brain imaging approaches and optogenetic manipulations are powerful tools to map brain-wide neural circuits in vivo. To date, functional magnetic resonance imaging (fMRI) provides the most comprehensive evaluation of such large-scale circuitry. However, functional ultrasound imaging (fUSI) has recently emerged as a complementary imaging modality that can extend such measurements towards the context of diverse behavioral states and tasks. Nevertheless, in order to properly interpret the fUSI signal during these complicated scenarios, it must first be carefully validated against well-established technologies, such as fMRI, in highly controlled experimental settings. Here, to address this need, we compared subsequent fMRI and fUSI recordings in response to direct neuronal activation via optogenetics in the same animals under an identical anesthetic protocol. Specifically, we applied various intensities of light stimulation to the primary motor cortex (M1) of mice and compared the spatiotemporal dynamics of the elicited fMRI and fUSI signals. Overall, our general linear model analysis (t-scores) and time series analysis (z-scores) revealed that fUSI was more sensitive than fMRI for detecting optogenetically-induced neuronal activation. Local field potential recordings in the bilateral M1 and striatum also better co-localized with fUSI activation patterns than those of fMRI. Finally, the fUSI response contained distinct arterial and venous components that provide vascular readouts of neuronal activity with vessel-type specificity.

A guide to using functional magnetic resonance imaging to study Alzheimer's disease in animal models.

Alzheimer's disease is a leading healthcare challenge facing our society today. Functional magnetic resonance imaging (fMRI) of the brain has played an important role in our efforts to understand how Alzheimer's disease alters brain function. Using fMRI in animal models of Alzheimer's disease has the potential to provide us with a more comprehensive understanding of the observations made in human clinical fMRI studies. However, using fMRI in animal models of Alzheimer's disease presents some unique challenges. Here, we highlight some of these challenges and discuss potential solutions for researchers interested in performing fMRI in animal models. First, we briefly summarize our current understanding of Alzheimer's disease from a mechanistic standpoint. We then overview the wide array of animal models available for studying this disease and how to choose the most appropriate model to study, depending on which aspects of the condition researchers seek to investigate. Finally, we discuss the contributions of fMRI to our understanding of Alzheimer's disease and the issues to consider when designing fMRI studies for animal models, such as differences in brain activity based on anesthetic choice and ways to interrogate more specific questions in rodents beyond those that can be addressed in humans. The goal of this article is to provide information on the utility of fMRI, and approaches to consider when using fMRI, for studies of Alzheimer's disease in animal models.