Mousecircuits.Org: an Online Repository to Guide the Circuit Era of Disordered Affect
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bioRxiv preprint doi: https://doi.org/10.1101/2020.02.16.951608; this version posted February 17, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. MouseCircuits.org: An online repository to guide the circuit era of disordered affect Kristin R. Anderson ID 1,2 and Dani Dumitriu ID 1,2 1Columbia University, Departments of Pediatrics and Psychiatry, New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY 10032 2Columbia University, Zuckerman Institute, 3227 Broadway, New York, NY 10027 Affective disorders rank amongst the most disruptive and tem and the gut microbiome (2,3). However, the mysteries of prevalent psychiatric diseases, resulting in enormous societal the brain, a structure with idiosyncratic and interconnected and economic burden, and immeasurable personal costs. Novel architecture, are unlikely to be revealed solely on the basis of therapies are urgently needed but have remained elusive. The this type of sledgehammer approach. era of circuit-mapping in rodent models of disordered affect, ushered in by recent technological advancements allowing for Enter the era of circuit dissection. In the last precise and specific neural control, has reenergized the hope for decade, groundbreaking technological advances have al- precision psychiatry. Here, we present a novel whole-brain cu- lowed neuroscientists to take control of neural firing with mulative network and critically access the progress made to- impressive precision and specificity (Figure 1) (4–7). An date on circuits mediating affective-like behaviors in rodents to seek unifying principles of this cumulative data. We identi- in-depth description of these tools is outside the scope of fied 106 original manuscripts in which optogenetics or chemo- this paper [see (4–8) for comprehensive descriptions]. Con- genetics were used to dissect behaviors related to fear-like, cisely, two techniques have fundamentally changed the land- depressive-like or anxiety-like behaviors in rodents. Focus- scape of neural circuit dissection: optogenetics, which con- ing on the 60 manuscripts that investigated pathways rather trols neuronal firing with light, and chemogenetics, which than regions, we identified emergent themes. We found that alters neuronal firing with otherwise biologically inert com- while a few pathways have been validated across similar be- pounds. Optogenetics uses genetically engineered transmem- haviors and multiple labs, the data is mostly disjointed, with brane channels that open in response to specific wavelengths evidence of bidirectional effects of several pathways. Addition- of light to allow selective passage of charged ions to either de- ally, there is a need for analysis informed by observation prior polarize or hyperpolarize targeted neurons. Chemogenetics to perturbation. Given the complex nature of brain connectiv- uses G-protein coupled receptors known as Designer Recep- ity, we argue that the compartmentalized viewpoint that devel- ops as a consequence of fragmented pathway-specific manip- tors Exclusively Activated by Designer Drugs (DREADDs) ulations does not readily lend itself to an integrative picture. to enhance or inhibit neuronal excitability in the presence To address this, we launched an interactive online consortium, of biologically inert compounds, such as clozapine N-oxide MouseCircuits.org, an open-source platform for consoli- (CNO). Both tools can selectively activate or inactivate neu- dated circuit data. This tool aims to support the shared vision rons of interest when combined with genetic labeling tech- of informed circuit dissection that ultimately leads to prevention niques. Optogenetic control provides high temporal preci- and treatment of human disorders. sion on scales relevant to manipulations of individual action potentials. Chemogenetic control acts on slower timescales Circuit | Optogenetics | Chemogenetics | Anxiety | Fear | Depression (minutes, hours, or days) but has the advantage of modulat- ing endogenous activity by placing the neuron in either a de- Correspondence: [email protected] polarized state, for increased excitability, or hyperpolarized state, for decreased excitability. The ERA OF CIRCUIT MAPPING Initial efforts used chemogenetic and optogenetic control of brain regions and confirmed findings from clas- Mood disorders account for most years lost to disability (1). sical lesion studies (ex: (9)). Rapid progress followed, There is an urgent need for new effective therapeutics, but with increasingly refined targeting of neurons based on translation of laboratory discoveries to treatments for human transcriptional-, projection- and/or activity-specificity (Fig- disorders has thus far proven difficult. Excitingly, we are ure 1). However, despite substantial amassed data, knowl- on the brink of a historical turning point. Until recently – edge of individual pathways exists largely in a realm that borrowing from groundbreaking advancement of other or- ignores the complexity of an interconnected whole-brain net- gan systems – mechanistic dissection of disordered affect has work. Therefore, at the moment, it is difficult to envision how targeted singular neurotransmitter systems, brain regions, or these findings can be translated to improve the prevention and genes. This approach enabled the understanding of the indi- treatment of human mental health conditions. The goal of this vidual building blocks of brain function and continues to be paper is therefore threefold: (1) Summarize the cumulative supported by novel theories involving global mechanism of knowledge of affective circuits obtained using chemogenetic affect disruption, implicating for example the immune sys- and optogenetic manipulations in animal models; (2) Criti- Anderson et al. | bioRχiv | February 16, 2020 | 1–20 bioRxiv preprint doi: https://doi.org/10.1101/2020.02.16.951608; this version posted February 17, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Table 1. Region names and abbreviations from the Allen Brain Atlas with cally assess the current state of the era of circuit mapping, its the expectation of the infralmibic cortex (IL rather than ILA) and the addition of the amygdala (Amyg), dorsal hippocampus (dHPC), ventral hippocampus promise and its perils; and (3) Introduce an online platform (vHPC), and medial prefrontal cortex (mPFC). to help consolidate and integrate rapidly growing neurocir- cuit data moving forward: MouseCircuits.org. Abbreviation Region Amyg Amygdala Neural map criteria ACC Anterior cingulate cortex Our goal was to develop a functional neural map of affec- Acx Auditor cortex tive state circuity data, enabled by chemogenetics and op- BLA Basolateral amygdala togenetics. We searched PubMed (accessed on November BST Bed nucleus of the stria terminalis 20th, 2019) for combinations of keywords referencing cir- CeA Central amygdala cuit dissection tools (e.g. “chemogenetics”, “optogenetics”, DG Dentate gyrus “DREADDs”) and keywords referencing affect (e.g. “fear”, DR Dorsal raphe nucleus “anxiety”, “depression”) or specific behavioral tests com- EC External capsule monly used to asses affective-like responses in rodents (e.g. H Hypothalamus “social defeat stress”, “elevated plus maze”, “tail suspen- HPF Hippocampus formation sion”). Studies on mouse and rats only were included. These dHPC Dorsal Hippocampus studies covered the investigation of circuits spanning 33 re- vHPC Ventral Hippocampus gions (Table 1). No date restrictions were used, but consis- AI Insula tent with chemogenetic and optogenetic tools’ recent devel- IL Infralimbic cortex opment, all 102 identified manuscripts were from 2010 or later (Table 2). An additional three manuscripts were identi- ILT Intralaminar thalamus fied based on Twitter updates of BioRxiv preprints, for a total LA Lateral amygdala of 106 reviewed studies (Table 2, page 18). LC Locus coeruleus LDT Laterodorsal tegmentum LH Lateral habenula LS Lateral septum MDT Mediodorsal nucleus of the thalamus DISSECTION OF RODENT CIRCUITS FOR mPFC Medial prefrontal cortex DISORDERED AFFECT ACB Nucleus accumbens NR Nucleus reuniens Inclusion criteria for neural manipulations PAG Periaqueductal gray A variety of tools can be used to manipulate neural activity PL Prelimbic cortex including electric stimulation and transcranial magnetic stim- PVT Dorsal midline thalamus ulation. For the purpose of the creation of this neural network PC Piriform cortex and guide, we restricted our search to studies in which opto- SC Superior colliculus genetics and/or chemogenetics were used to manipulate neu- T Thalamus (including MFD) ronal function, as these tools, when combined with genetic VTA Ventral tegmental area labeling, offer unprecedented specificity and control of mi- VS Ventral striatum crocircuits. Inclusion criteria for rodent behaviors The relevance and success of rodent models for studying were not included) but targeted three types of behavioral re- human mental health diseases is currently fiercely debated sponses in rodents: “fear-like” (innate or learned), “anxiety- (2,10–18). It is well-established that animal models can- like”, and “depressive-like” (Figure 2). These behaviors and not recapitulate