Applications of chemogenetics in non-human primates

Raper, Jessica; Galván, Adriana

doi:10.1016/j.coph.2022.102204

Cited by 25 publications

(14 citation statements)

References 86 publications

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“…In addition, other DREADD agonists are also promising, and should be similarly tested empirically. For example, compound 21 (Ferrari et al, 2022; Jendryka et al, 2019; Kljakic et al, 2022; Thompson et al, 2018), perlapine (Chen et al, 2015; Kljakic et al, 2022; Thompson et al, 2018), DCZ (Nagai et al, 2020; Nentwig et al, 2022; Raper and Galvan, 2022; Upright and Baxter, 2020), and olanzapine (Goossens et al, 2021; Upright and Baxter, 2020; Weston et al, 2019) have been reported to have strong and selective effects at DREADDs, without pronounced off-target actions. We hope that the field will soon converge upon the “best” DREADD agonist for most behavioral experiments.…”

Section: Discussionmentioning

confidence: 99%

A head-to-head comparison of two DREADD agonists for suppressing operant behavior in rats via VTA dopamine neuron inhibition

Lawson

Ruiz

Mahler

2023

Preprint

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Rationale: Designer receptors exclusively activated by designer drugs (DREADDs) are a tool for remote control of defined neuronal populations during behavior. These receptors are inert unless bound by an experimenter-administered designer drug, most commonly clozapine-n-oxide (CNO). However, questions have emerged about the suitability of CNO as a systemically administered DREADD agonist. Objectives: Second-generation agonists such as JHU37160 (J60) have been developed, which may have more favorable properties than CNO. Here we sought to directly compare effects of CNO (0, 1, 5, & 10 mg/kg, i.p.) and J60 (0, 0.03, 0.3, & 3 mg/kg, i.p.) on operant food pursuit. Methods: Male and female TH:Cre+ rats and their wildtype (WT) littermates received cre-dependent hM4Di-mCherry vector injections into ventral tegmental area (VTA), causing inhibitory DREADD expression in VTA dopamine neurons in TH:Cre+ rats. Rats were trained to stably lever press for palatable food on a fixed ratio 10 schedule, and doses of both agonists were tested on separate days in a counterbalanced order. Results: All three CNO doses reduced operant food seeking in rats with DREADDs, and no CNO dose had behavioral effects in WT controls. The highest tested J60 dose significantly reduced responding in DREADD rats, but this dose also increased responding in WTs, indicating non-specific effects. The magnitude of CNO and J60 effects in TH:Cre+ rats were correlated and were present in both sexes. Conclusions: Findings demonstrate the usefulness of directly comparing DREADD agonists when optimizing behavioral chemogenetics, and highlight the importance of proper controls, regardless of the DREADD agonist employed.

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Section: Discussionmentioning

confidence: 99%

A head-to-head comparison of two DREADD agonists for suppressing operant behavior in rats via VTA dopamine neuron inhibition

Lawson

Ruiz

Mahler

2023

Preprint

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“…There have been few studies using DREADDs in non-human primates thus far, and these have been primarily limited to proof of principle studies or studies investigating sensory processing or cognitive decision making ( 35 – 37 ). In the current study, whilst aiming to recapitulate core aspects of affective disorders ( 38 ) with the prototypic activator CNO, we also used a new DREADD activator, deschloroclozapine, that enabled high efficacy at low doses ( 39 ), further supporting our dissection of the specific pathways mediating distinct symptom domains.…”

Section: Discussionmentioning

confidence: 99%

Chemogenetics identifies separate area 25 brain circuits involved in anhedonia and anxiety in marmosets

et al. 2023

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Poor outcomes are common in individuals with anxiety and depression, and the brain circuits underlying symptoms and treatment responses remain elusive. To elucidate these neural circuits, experimental studies must specifically manipulate them, which is only possible in animals. Here, we used a chemogenetics strategy involving engineered designer receptors exclusively activated by designer drugs (DREADDs) to activate a region of the marmoset brain that is dysfunctional in human patients with major depressive disorder, called the subcallosal anterior cingulate cortex area 25 (scACC-25). Using this DREADDs system, we identified separate scACC-25 neural circuits that underlie specific components of anhedonia and anxiety in marmosets. Activation of the neural pathway connecting the scACC-25 to the nucleus accumbens (NAc) caused blunting of anticipatory arousal (a form of anhedonia) in marmosets in response to a reward-associated conditioned stimulus in an appetitive Pavlovian discrimination test. Separately, activation of the circuit between the scACC-25 and the amygdala increased a measure of anxiety (the threat response score) when marmosets were presented with an uncertain threat (human intruder test). Using the anhedonia data, we then showed that the fast-acting antidepressant ketamine when infused into the NAc of marmosets prevented anhedonia after scACC-25 activation for more than 1 week. These neurobiological findings provide targets that could contribute to the development of new treatment strategies.

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“…On the other hand, these techniques have not been widely implemented in non-human primate models. The primate neuroscientific community has only scantly published on neuronal actuator and indicator techniques 1–3,43,44 . Furthermore, actuator and indicator efficacy remains largely unreliable and ineffective in one or more of the important categories for defining its success (i.e.…”

Section: Discussionmentioning

confidence: 99%

Direct comparison of epifluorescence and immunostaining for assessing viral mediated gene expression in the primate brain

Daw

El-Nahal

Basso

et al. 2022

Preprint

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Viral vector technologies are commonly used in neuroscience research to understand and manipulate neural circuits, but successful applications of these technologies in non-human primate models have been inconsistent. An essential component to improve these technologies is an impartial and accurate assessment of the effectiveness of different viral constructs in the primate brain. We tested a diverse array of viral vectors delivered to the brain and extraocular muscles of macaques and compared three methods for histological assessment of viral-mediated fluorescent transgene expression: epifluorescence (Epi), immunofluorescence (IF), and immunohistochemistry (IHC). Importantly, IF and IHC identified a greater number of transduced neurons compared to Epi. Furthermore, IF and IHC reliably provided enhanced visualization of transgene in most cellular compartments (i.e., dendritic, axonal, and terminal fields), whereas the degree of labeling provided by Epi was inconsistent and predominantly restricted to somas and apical dendrites. Because Epi signals are unamplified (in contrast to IF and IHC), Epi likely provides a more veridical assessment for the amount of accumulated transgene and, thus, the potential to chemo- or optogenetically manipulate neuronal activity. The comparatively weak Epi signals suggest that the current generations of viral constructs, regardless of delivered transgene, are not optimized for primates. This reinforces an emerging viewpoint that viral vectors tailored for the primate brain are necessary for basic research and human gene therapy.

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Applications of chemogenetics in non-human primates

Cited by 25 publications

References 86 publications

A head-to-head comparison of two DREADD agonists for suppressing operant behavior in rats via VTA dopamine neuron inhibition

A head-to-head comparison of two DREADD agonists for suppressing operant behavior in rats via VTA dopamine neuron inhibition

Chemogenetics identifies separate area 25 brain circuits involved in anhedonia and anxiety in marmosets

Direct comparison of epifluorescence and immunostaining for assessing viral mediated gene expression in the primate brain

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