Ancestral Circuits for the Coordinated Modulation of Brain State

Abstract

SUMMARY Internal states of the brain profoundly influence behavior. Fluctuating states such as alertness can be governed by neuromodulation, but the underlying mechanisms and cell types involved are not fully understood. We developed a method to globally screen for cell types involved in behavior by integrating brain-wide activity imaging with high-content molecular phenotyping and volume registration at cellular resolution. We used this method (MultiMAP) to record from 22 neuromodulatory cell types in behaving zebrafish during a reaction-time task that reports alertness. We identified multiple monoaminergic, cholinergic, and peptidergic cell types linked to alertness and found that activity in these cell types was mutually correlated during heightened alertness. We next recorded from and controlled homologous neuromodulatory cells in mice; alertness-related cell-type dynamics exhibited striking evolutionary conservation and modulated behavior similarly. These experiments establish a method for unbiased discovery of cellular elements underlying behavior and reveal an evolutionarily conserved set of diverse neuromodulatory systems that collectively govern internal state.

Multiple overlapping hypothalamus-brainstem circuits drive rapid threat avoidance

“…Our brain-wide and hypothalamic cell typespecific imaging data both point towards a similar principle: neural activity patterns are widely distributed across cell types and brain areas, even during simple behaviors. These types of widespread activity patterns have been observed in other studies that use large-scale cellular activity recordings across the nervous system (Wu et al, 1994;Ahrens et al, 2012;Kato et al, 2015;Lovett-Barron et al, 2017;Allen et al, 2019). While it is unlikely that every neuron active during a given behavior is required for its execution, it is not known whether such distributed activity is an incidental consequence of dense connectivity or reflects an important role in enforcing the reliability of common behaviors (Edelman & Gally, 2001).…”

“…To determine which brain regions are involved in rapid stressoravoidance responses in zebrafish, we performed brain-wide two-photon Ca 2+ imaging in fish with pan-neuronal expression of GCaMP6s (Tg(elavl3:H2B-GCaMP6s), Vladimirov et al, 2014) as they responded to the onset of environmental stressors (Figure 2a,b, Figure S2a, Methods). To provide an avoidance-promoting stimulus independent of homeostatic stress, we also included a visual looming stimulus (Temizer et al, 2015;Dunn et al, 2016;Lovett-Barron et al, 2017). .…”

“…Brain-wide cellular-resolution Ca 2+ imaging revealed distributed representations of stressor detection and resultant motor action, with notable stimulus-encoding in the preoptic hypothalamus -a neurosecretory region homologous to the paraventricular hypothalamus in mammals (Herget et al, 2014;Biran et al, 2015; and well-known to be involved in slow homeostatic adaptation (Joëls & Baram, 2009;Ulrich-Lai & Herman, 2009;Herman & Tasker, 2016). To explore the neuronal dynamics of molecularly-defined cell types within the hypothalamus during this behavior, we extended a method we had previously developed (MultiMAP; Lovett-Barron et al, 2017) to enable the cellular-resolution alignment of neural activity imaging to multiplexed gene expression. We developed and applied a next-generation form of this method to record from six to nine cell types at once, defined by the expression of genes for neuropeptide transmitters.…”

Microbiota–modulated enteric neuron translational profiling uncovers a CART+ glucoregulatory subset

“…Because these neuropeptides are known to be expressed both in the periphery(25)(26)(27)(28)(29) and CNS (24), we used a local viral delivery approach to target these neurons and avoid CNS effects. Injection of retrograde adeno-associated virus (AAVrg)-FLEX-tdTomato (30) revealed a prominent population of tdTomato+ neurons in the ileum, and colon myenteric plexus of Cartpt Cre(31) and Npy Cre (32) mice(Fig. 4A, fig.…”

Ready, set, go: the bridging of attention to action by acetylcholine in prefrontal cortex

“…Likewise, much is still unknown about the cellular mechanisms necessary to move from active monitoring to action. Studies in awake, behaving organisms are increasingly feasible, including the mapping and interrogation of cholinergic signalling with in vivo multiphoton imaging or light-sheet microscopy in zebrafish -where a conserved role for acetylcholine in mediating arousal has recently been shown (Lovett-Barron et al 2017) -or with fibre photometry in rodents. Such experiments permit the identification of behaviourally relevant circuits and the sequence of their activation.…”