Circuit dynamics of adaptive and maladaptive behaviour

Abstract

The recent development of technologies for investigating specific components of intact biological systems has allowed elucidation of the neural circuitry underlying adaptive and maladaptive behaviours. Investigators are now able to observe and control, with high spatio-temporal resolution, structurally defined intact pathways along which electrical activity flows during and after the performance of complex behaviours. These investigations have revealed that control of projection-specific dynamics is well suited to modulating behavioural patterns that are relevant to a broad range of psychiatric diseases. Structural dynamics principles have emerged to provide diverse, unexpected and causal insights into the operation of intact and diseased nervous systems, linking form and function in the brain.

Figure 1. Visualizing projections in the intact mammalian brain

The entire mouse brain has been processed with CLARITY^, (with Thy-1 type projection neurons labelled in green); such brain wide structural data sets may be integrated with other data streams from the same animal, including activity records during behaviour (as obtained with GECIs), stable activity markers such as immediate-early genes, whole-mount molecular phenotyping, behavioural scores in the presence or absence of optogenetic or disease-model interventions, and opsin–fluorophore expression patterns. In general, whole-brain analysis is useful for interpretation; for example, use with multiple retrograde labels may help to determine whether individual cells include collaterals projecting to multiple sites, an important consideration in projection targeting. Adapted with permission from ref. .

Figure 2. Controlling projections in the intact mammalian brain

Behavioural state assembly and complexity can be assessed with projection targeting. Functional organization of the bed nucleus of the stria terminalis (BNST) circuitry is shown. The oval nucleus of the BNST (ovBNST) is anxiogenic, and the anterodorsal BNST (adBNST) is anxiolytic, as is the projection from the BLA (red arrows); the ovBNST may act to increase anxiety by inhibiting the adBNST or by independently influencing downstream structures. The adBNST projects to the ventral tegmental area (VTA), lateral hypothalamus (LH) and parabrachial nucleus (PB); each of these projections decreases a distinct feature of anxiety expression, and coordinated recruitment of these subpopulations may be implemented by recurrent circuitry in adBNST. Projections are assessed by introduction of opsin (needle) into the adBNST, and independent targeting of fibre-optic interfaces depicted for each candidate downstream target (blue arrows). Here (as with medial prefrontal cortex projections and VTA projections) little mixed-site collateralization from single neurons is seen. Adapted with permission from ref. .