a-micro-ct-based-method-for-characterizing-lesions-locating

A Micro-CT-based Method for Characterizing Lesions and Locating Electrodes in Small Animal Brains

Lesion and electrode location verification are traditionally done via histological examination of stained brain slices, a time-consuming procedure that ...

Harvard University

Although a wealth of data have elucidated the structure and physiology of neuronal circuits, we still only have a very limited understanding of how behavioral learning is implemented at the network level. An emerging crucial player in this implementation is disinhibition--a transient break in the balance of excitation and inhibition. In contrast to the widely held view that the excitation/inhibition balance is highly stereotyped in cortical circuits, recent findings from behaving animals demonstrate that salient events often elicit disinhibition of projection neurons that favors excitation and thereby enhances their activity. Behavioral functions ranging from auditory fear learning, for which most data are available to date, to spatial navigation are causally linked to disinhibition in different compartments of projection neurons, in diverse cortical areas and at timescales ranging from milliseconds to days, suggesting that disinhibition is a conserved circuit mechanism contributing to learning and memory expression.

Disinhibition, a Circuit Mechanism for Associative Learning and Memory.

Rapid and reversible manipulations of neural activity in behaving animals are transforming our understanding of brain function. An important assumption underlying much of this work is that evoked behavioural changes reflect the function of the manipulated circuits. We show that this assumption is problematic because it disregards indirect effects on the independent functions of downstream circuits. Transient inactivations of motor cortex in rats and nucleus interface (Nif) in songbirds severely degraded task-specific movement patterns and courtship songs, respectively, which are learned skills that recover spontaneously after permanent lesions of the same areas. We resolve this discrepancy in songbirds, showing that Nif silencing acutely affects the function of HVC, a downstream song control nucleus. Paralleling song recovery, the off-target effects resolved within days of Nif lesions, a recovery consistent with homeostatic regulation of neural activity in HVC. These results have implications for interpreting transient circuit manipulations and for understanding recovery after brain lesions. 

Acute off-target effects of neural circuit manipulations.

Lesion verification and quantification is traditionally done via histological examination of sectioned brains, a time-consuming process that relies heavily on manual estimation. Such methods are particularly problematic in posterior cortical regions (e.g. visual cortex), where sectioning leads to significant damage and distortion of tissue. Even more challenging is the post hoc localization of micro-electrodes, which relies on the same techniques, suffers from similar drawbacks and requires even higher precision. Here, we propose a new, simple method for quantitative lesion characterization and electrode localization that is less labor-intensive and yields more detailed results than conventional methods. We leverage staining techniques standard in electron microscopy with the use of commodity micro-CT imaging. We stain whole rat and zebra finch brains in osmium tetroxide, embed these in resin and scan entire brains in a micro-CT machine. The scans result in 3D reconstructions of the brains with section thickness dependent on sample size (12-15 and 5-6 microns for rat and zebra finch respectively) that can be segmented manually or automatically. Because the method captures the entire intact brain volume, comparisons within and across studies are more tractable, and the extent of lesions and electrodes may be studied with higher accuracy than with current methods.

Article	Year
Disinhibition, a Circuit Mechanism for Associative Learning and Memory. Neuron\| PubMed ID: 26494276	2015
Acute off-target effects of neural circuit manipulations. Nature\| PubMed ID: 26649821	2015
A micro-CT-based method for quantitative brain lesion characterization and electrode localization. Scientific reports\| PubMed ID: 29581439	2018

Steffen B.E. Wolff

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