Acute off-target effects of neural circuit manipulations

Abstract

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.

How Close Are We to Understanding What (if Anything) γ Oscillations Do in Cortical Circuits?

“…This issue is not unique to ␥ oscillations. Electrical microstimulation and optogenetic stimulation, which often purport to selectively increase or decrease spiking within one brain region or cell type, invariably elicit numerous unintended effects (e.g., altered activity in interconnected cell types and brain regions) (Otchy et al, 2015). Indeed, any manipulation that increases the firing of cortical excitatory neurons is almost certain to also increase ␥ oscillations.…”

Role of a Lateral Orbital Frontal Cortex-Basolateral Amygdala Circuit in Cue-Induced Cocaine-Seeking Behavior

“…This unexpected finding may have resulted from possible offtarget effects of our optogenetic manipulation (see review by Otchy et al, 2015). Mitigating this possibility, previous localization studies that utilized NMDA lesions, or tetrodotoxin-induced or lidocaine-induced neural inactivation, targeted BLA neurons in general (Grimm and See, 2000;Kantak et al, 2002;Meil andSee, 1997,Whitelaw et al, 1996).…”

Bilateral neurotoxic lesions in NCM before tutoring onset do not prevent successful tutor song learning

“…Given that London et al injected identical volumes of pharmacological agent as we did, it is unlikely that our manipulation affected smaller portions of NCM than were affected in their study (note that we are not aware of any NCM-manipulation study in which injected volumes were larger than in our study). A possible explanation for the discrepancy with [9] could be an indirect effect of the transient manipulation, triggering a homeostatic imbalance of downstream circuits, as reported in [10]for a different brain area. That is, the impact of transient inactivation of NCM on song learning could be a result of disrupting downstream areas instead of a more direct involvement of NCM in tutor song memorization.…”

“…The causal evidence comes from pharmacological manipulations, which reveal that transiently suppressing the extracellular signal-regulated kinase signaling pathway in NCM, specifically during tutoring, severely impairs song learning [9]. To probe for possible behavioral differences between transient and irreversible brain manipulations [10], we test whether NCM neural circuits are required in their full integrity for successful memorization of tutor song. We perform large irreversible and bilateral lesions in NCM of very young birds before we start tutoring them.…”