Contemporary strategies for dissecting the neuronal basis of neurodevelopmental disorders

Dong oh Seo; Laura E. Motard; Michael R. Bruchas

doi:10.1016/j.nlm.2018.03.015

Contemporary strategies for dissecting the neuronal basis of neurodevelopmental disorders

Dong oh Seo, Laura E. Motard, Michael R. Bruchas

Division of Aging & Dementia

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

Great efforts in clinical and basic research have shown progress in understanding the neurobiological mechanisms of neurodevelopmental disorders, such as autism, schizophrenia, and attention-deficit hyperactive disorders. Literature on this field have suggested that these disorders are affected by the complex interaction of genetic, biological, psychosocial and environmental risk factors. However, this complexity of interplaying risk factors during neurodevelopment has prevented a complete understanding of the causes of those neuropsychiatric symptoms. Recently, with advances in modern high-resolution neuroscience methods, the neural circuitry analysis approach has provided new solutions for understanding the causal relationship between dysfunction of a neural circuit and behavioral alteration in neurodevelopmental disorders. In this review we will discuss recent progress in developing novel optogenetic and chemogenetic strategies to investigate neurodevelopmental disorders.

Original language	English
Article number	106835
Journal	Neurobiology of Learning and Memory
Volume	165
DOIs	https://doi.org/10.1016/j.nlm.2018.03.015
State	Published - Nov 2019

Keywords

Autism
Chemogenetics
IDD
Neurodevelopment
Optogenetics
Schizophrenia

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10.1016/j.nlm.2018.03.015

Cite this

@article{123552d7f5ee4862a2d70d7f472aa73b,

title = "Contemporary strategies for dissecting the neuronal basis of neurodevelopmental disorders",

abstract = "Great efforts in clinical and basic research have shown progress in understanding the neurobiological mechanisms of neurodevelopmental disorders, such as autism, schizophrenia, and attention-deficit hyperactive disorders. Literature on this field have suggested that these disorders are affected by the complex interaction of genetic, biological, psychosocial and environmental risk factors. However, this complexity of interplaying risk factors during neurodevelopment has prevented a complete understanding of the causes of those neuropsychiatric symptoms. Recently, with advances in modern high-resolution neuroscience methods, the neural circuitry analysis approach has provided new solutions for understanding the causal relationship between dysfunction of a neural circuit and behavioral alteration in neurodevelopmental disorders. In this review we will discuss recent progress in developing novel optogenetic and chemogenetic strategies to investigate neurodevelopmental disorders.",

keywords = "Autism, Chemogenetics, IDD, Neurodevelopment, Optogenetics, Schizophrenia",

author = "Seo, {Dong oh} and Motard, {Laura E.} and Bruchas, {Michael R.}",

note = "Funding Information: We thank Skylar M. Spangler for comments on the manuscript. This work was supported by National Institute of Health Grants: NIH R01MH112355 , and BRAIN Initiative 1U01 MH10913301 . Funding Information: As described above, the current approach on neuropsychiatric disorders has been moving from large-scale correlational studies using large data analysis to investigate gene and protein expression patterns in the brain and behavioral patterns, such as behavioral genomics, to a neural circuit analysis for understanding dysfunction in neurodevelopmental disorders ( Jazayeri & Afraz, 2017 ). This transition has also been influenced by novel engineering approaches and unique biological tools necessary to better understand these neurobiological questions. This type of research requires a careful transition between new biological questions and developing new tools to overcome the limitation of existing tools, and mechanistic interpretations. There are several limitations and factors that need to be carefully considered in experimental design before getting started using these new tools. For example, in optogenetics, laser intensity and duration of delivery to a target area via fiber optics should be carefully adjusted, considering that high intensity and/or long-lasting laser application may cause brain tissue damage or alter physiological properties through changing brain tissue temperature ( Stujenske, Spellman, & Gordon, 2015 ). The intensity of the laser is also a factor that determines the possible range that can be studied in the target of interest (i.e. higher intensity light will spread to a wider area). This factor is more important in projection-targeting experiments compared to cell body-targeting experiments, because in some cases, collateral axonal projections are widely spread, and it is difficult to activate opsins in a small focal area with traditional fiber optics. Recently, to limit unexpected light diffusion - longer wavelength devices and opsins that can penetrate deeper into the brain have been developed. These can deliver light to a limited focal area, a new fiber optic has been developed ( Al-Hasani et al., 2015; Pisanello et al., 2017; Shin et al., 2017 ). Generally, projection-targeting experiments present more obstacles. The opsins in the long-range axonal terminal will take longer to express fully (e.g. 6 weeks after virus injection). Also, axonal optogenetic stimulation (or non-specific en passant stimulation) may cause antidromic spiking to the cell body and eventually activate collateral axon-terminals that branch out from the cell body ( Jennings et al., 2013 ). In this case, it is difficult to interpret behavioral changes as an outcome of specific terminal activation within a region. Systemic analysis combining electrophysiology and immediate early gene expression, or measured with electrophysiology and pharmacology presents a possible solution to rule out the possibility that an upstream brain region is affected by optogenetic stimulation. Also, a recent development of high efficient retrograde access to projection neurons from a certain terminal region allows the control of specific efferent projection by activating cell-body region ( Tervo et al., 2016 ). This approach can be additional solution to the issues related to terminal stimulation that are discussed above. In addition, the many physiological characterizations of optogenetic tools have been tested in vitro . The characterization of those tools could be different in vivo depending on neural connectivity, the level of viral expression, and light delivery. Therefore, careful adjustment of the factors and in vivo re-characterization should be considered before embarking on using these tools for testing a particular hypothesis. Further efforts are needed to improve inhibitory optogenetic tools ( Kim et al., 2017; Wiegert et al., 2017 ). The current versions of inhibitory opsins (Cl − pump: NpHR or H + pumps: Arch) are relatively less efficient compared to excitatory opsin channels. In addition, they present some consistency issues ( Mahn, Prigge, Ron, Levy, & Yizhar, 2016; Raimondo, Kay, Ellender, & Akerman, 2012 ). For example, silencing the activity of neurons with NpHR can increase the probability of synaptically-evoked spiking following the termination of photoactivation ( Raimondo et al., 2012 ), but this does not occur when using Arch. However, photoactivation in axons with Arch leads to increased spontaneous neurotransmitter release 2–3 minitues after photoactivation ( Mahn et al., 2016 ). GPCR-based optogenetics (opto-XR) has not been assessed for these particular issues, but could also be a potential solution ( Spangler & Bruchas, 2017; Siuda, Copits et al., 2015; Siuda, McCall et al., 2015 ) given that many GPCRs effectively inhibit release of transmitters from presynaptic terminals in vivo, within endogenous circuits. When using chemogenetic DREADD-based systems, new concerns have arisen over CNO (DREADD actuator) usage ( Gomez et al., 2017 ). Recently, Gomez et al. (2017) reported that upon systemic injection of CNO, the CNO first rapidly converts to clozapine, which is a chemical form of antipsychotic medication that binds serotonin and dopamine receptors, and then enters the central nervous system, which is followed by binding to CNS-expressed DREADDs. This finding demands careful interpretation of results from past DREADD studies. Authors suggest using subthreshold doses of clozapine instead of CNO as an actuator. However, because there could be potential off-target effects elicited by clozapine itself, proper DREADD null CNO-injected controls are necessary in order to draw reliable conclusions (e.g. low doses of clozapine in the absence of the designer receptors) ( Mahler & Aston-Jones, 2018 ). In this review, we focused on modern tools to manipulate neural circuits, but there are increasing attempts to integrate these neural-control tools with techniques for monitoring neural activity and tagging activated cells, such as Ca 2+ imaging and neural tagging to reactivate specific populations of cells that were previously activated ( Carrillo-Reid, Yang, Kang Miller, Peterka, & Yuste, 2017; Liu et al., 2012 ). For integrating optogenetics with Ca 2+ imaging, opsins should be carefully selected, and fluorescent light intensity and wavelength sensitive of the opsin should be tightly titrated to avoid cross-stimulation of opsins by fluorescent light during Ca 2+ imaging. For example, fluorescent light for Green Fluorescent-Calmodulin Protein (GCaMP) imaging can partially activate blue-shifted opsins and also red-shifted opsins. Integrating chemogenetics with Ca 2+ imaging is an alternative option albeit with limited spatiotemporal advantages, but future generations of engineered opsins and Ca 2+ sensors will likely resolve these issues. Recently engineered concurrent detection of elevated calcium and light in a living cell will lead to the development of new tools to “tag” specific populations of cells activated within a specific time window, which would allow the targeted neurons to be controlled by optogenetics or chemogenetics at a later time point ( Wang et al., 2017 ). This tagging technique can be useful in developmental studies to track certain populations of cells tagged in an early stage of development and then investigate their function in later life. For instance, a certain population of neural ensembles that are activated by early life stress/traumatic event can be re-activated or inhibited to test if that particular ensemble is involved in shaping neurodevelopmental disorders (e.g. SSD, ASD, PTSD) ( Kerns, Newschaffer, & Berkowitz, 2015; Sch{\"a}fer et al., 2012 ). As described above, the recent findings using these new tools provides evidence of the functional relevance of brain circuitry to disease, but some studies have even demonstrated functional rescue in mutant mice. These findings underpin the potential utility of optogenetics and chemogenetics as potentially useful for developing therapeutic applications in human patients ( Gilbert, Harris, & Kapsa, 2014 ). However, there are some considerations and challenges which must be addressed before moving into human applications. First, these techniques are still highly invasive medical procedures. It would be challenging to express opsins or designer receptor genes into adult human neurons within a specific brain area, given the known limitations of gene therapy. In particular, for optogenetic application, effective large fiber optics would have to be designed on a human scale with a sufficient light source. The recent progress in developing wireless options using miniaturized, thin, flexible optoelectronic implants is a promising advance ( Shin et al., 2017 ). The other issue regarding human application of these tools is that most current neural circuitry studies apply optogenetic and chemogenetic tools for acute treatment. These techniques are still poorly understood in terms of their stability and impact following chronic stimulation and/or long term expression in cells and neurons. For instance, there is a lack of information regarding cellular health with long-term virus expression or chronic repeated photo- or chemical activation of neurons. There will certainly be further technological advancement in optogenetics and chemogenetics as the National Institutes of Health and National Science Foundation BRAIN initiatives continue to invest in new tools for dissecting brain function; undoubtedly this will lend several new tools for exploring psychiatric dysfunction. Lastly, in parallel with technological developments to control neural circuits, systematic evaluation of behavioral tests is of great importance in making careful interpretations and conclusions with results of optogenetic and chemogenetic circuit manipulations. Although the contemporary tools that we have discussed above offer a highly sophisticated approach to controlling neural circuits, the way the field translates the function of a circuit is ultimately based on outcomes of behavioral changes. Unfortunately, most behavioral tests have an inherent complexity (i.e. multiple cognitive/motivational factors could affect a single behavior test), and it can be difficult to draw a clear conclusion with a simple behavior test and measurement in rodents. For example, as we discussed above, most literature in this field uses rodent social interaction tests controlling a targeted-circuit, to claim that the targeted-circuit is involved in social dysfunction that is a common phenotype of many psychiatric disorders including ASD and SSD ( Cho & Sohal, 2014; Krishnan et al., 2017; Yizhar et al., 2011 ). In the standard social interaction test, animals explore a chamber where conspecific animals are constrained under a mashed cup, and their exploration time with the constrained mice is measured. However, human social behavior is much more complex, and measuring exploration time, even without contacts between animals in the test, provides only limited insights into social behavior ( H{\aa}nell & Marklund, 2014 ). That is, it is not clear if the circuit manipulation affected only the recognition/memory of a conspecific animal or changed their social interest/communication within the measurement. Measuring a complimentary rich suite of other social behaviors such as sniffing, playing, and ultrasonic vocalization would help make a stronger interpretations of the circuit manipulation and assist in finding adequate matches to known phenotypic traits of psychiatric disorders. Also, it is often important to test behaviors combining optogenetic and chemogenetic controls with etiologically relevant pharmacological treatment. For example, in the OCD study mentioned above, Ahmari et al. (2013) showed that cortico-striatal optogenetic stimulation increased self-grooming behavior. However, it may not necessarily implicate an emotion-related circuit mechanism of OCD (i.e. it could be just increment of motor function related to the pattern of grooming behavior). In the study, the authors showed that the excessive grooming behavior evoked by optogenetic stimulation was reversed by chronic fluoxetine treatment that is used as a first-line OCD treatment. Therefore, rigorous behavioral testis using parallel classical and contemporary neural control tools are demanded. Also, it is important to continue developing additional behavioral models that more realistically reflect clinical behavioral traits; and further developments in machine – learning to measure behavioral outcomes in non-biased ways are at the forefront of some of this research ( Wiltschko et al., 2015 ). 5 Funding Information: We thank Skylar M. Spangler for comments on the manuscript. This work was supported by National Institute of Health Grants: NIH R01MH112355, and BRAIN Initiative 1U01 MH109133. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

year = "2019",

month = nov,

doi = "10.1016/j.nlm.2018.03.015",

language = "English",

volume = "165",

journal = "Neurobiology of Learning and Memory",

issn = "1074-7427",

}

TY - JOUR

T1 - Contemporary strategies for dissecting the neuronal basis of neurodevelopmental disorders

AU - Seo, Dong oh

AU - Motard, Laura E.

AU - Bruchas, Michael R.

N1 - Funding Information: We thank Skylar M. Spangler for comments on the manuscript. This work was supported by National Institute of Health Grants: NIH R01MH112355 , and BRAIN Initiative 1U01 MH10913301 . Funding Information: As described above, the current approach on neuropsychiatric disorders has been moving from large-scale correlational studies using large data analysis to investigate gene and protein expression patterns in the brain and behavioral patterns, such as behavioral genomics, to a neural circuit analysis for understanding dysfunction in neurodevelopmental disorders ( Jazayeri & Afraz, 2017 ). This transition has also been influenced by novel engineering approaches and unique biological tools necessary to better understand these neurobiological questions. This type of research requires a careful transition between new biological questions and developing new tools to overcome the limitation of existing tools, and mechanistic interpretations. There are several limitations and factors that need to be carefully considered in experimental design before getting started using these new tools. For example, in optogenetics, laser intensity and duration of delivery to a target area via fiber optics should be carefully adjusted, considering that high intensity and/or long-lasting laser application may cause brain tissue damage or alter physiological properties through changing brain tissue temperature ( Stujenske, Spellman, & Gordon, 2015 ). The intensity of the laser is also a factor that determines the possible range that can be studied in the target of interest (i.e. higher intensity light will spread to a wider area). This factor is more important in projection-targeting experiments compared to cell body-targeting experiments, because in some cases, collateral axonal projections are widely spread, and it is difficult to activate opsins in a small focal area with traditional fiber optics. Recently, to limit unexpected light diffusion - longer wavelength devices and opsins that can penetrate deeper into the brain have been developed. These can deliver light to a limited focal area, a new fiber optic has been developed ( Al-Hasani et al., 2015; Pisanello et al., 2017; Shin et al., 2017 ). Generally, projection-targeting experiments present more obstacles. The opsins in the long-range axonal terminal will take longer to express fully (e.g. 6 weeks after virus injection). Also, axonal optogenetic stimulation (or non-specific en passant stimulation) may cause antidromic spiking to the cell body and eventually activate collateral axon-terminals that branch out from the cell body ( Jennings et al., 2013 ). In this case, it is difficult to interpret behavioral changes as an outcome of specific terminal activation within a region. Systemic analysis combining electrophysiology and immediate early gene expression, or measured with electrophysiology and pharmacology presents a possible solution to rule out the possibility that an upstream brain region is affected by optogenetic stimulation. Also, a recent development of high efficient retrograde access to projection neurons from a certain terminal region allows the control of specific efferent projection by activating cell-body region ( Tervo et al., 2016 ). This approach can be additional solution to the issues related to terminal stimulation that are discussed above. In addition, the many physiological characterizations of optogenetic tools have been tested in vitro . The characterization of those tools could be different in vivo depending on neural connectivity, the level of viral expression, and light delivery. Therefore, careful adjustment of the factors and in vivo re-characterization should be considered before embarking on using these tools for testing a particular hypothesis. Further efforts are needed to improve inhibitory optogenetic tools ( Kim et al., 2017; Wiegert et al., 2017 ). The current versions of inhibitory opsins (Cl − pump: NpHR or H + pumps: Arch) are relatively less efficient compared to excitatory opsin channels. In addition, they present some consistency issues ( Mahn, Prigge, Ron, Levy, & Yizhar, 2016; Raimondo, Kay, Ellender, & Akerman, 2012 ). For example, silencing the activity of neurons with NpHR can increase the probability of synaptically-evoked spiking following the termination of photoactivation ( Raimondo et al., 2012 ), but this does not occur when using Arch. However, photoactivation in axons with Arch leads to increased spontaneous neurotransmitter release 2–3 minitues after photoactivation ( Mahn et al., 2016 ). GPCR-based optogenetics (opto-XR) has not been assessed for these particular issues, but could also be a potential solution ( Spangler & Bruchas, 2017; Siuda, Copits et al., 2015; Siuda, McCall et al., 2015 ) given that many GPCRs effectively inhibit release of transmitters from presynaptic terminals in vivo, within endogenous circuits. When using chemogenetic DREADD-based systems, new concerns have arisen over CNO (DREADD actuator) usage ( Gomez et al., 2017 ). Recently, Gomez et al. (2017) reported that upon systemic injection of CNO, the CNO first rapidly converts to clozapine, which is a chemical form of antipsychotic medication that binds serotonin and dopamine receptors, and then enters the central nervous system, which is followed by binding to CNS-expressed DREADDs. This finding demands careful interpretation of results from past DREADD studies. Authors suggest using subthreshold doses of clozapine instead of CNO as an actuator. However, because there could be potential off-target effects elicited by clozapine itself, proper DREADD null CNO-injected controls are necessary in order to draw reliable conclusions (e.g. low doses of clozapine in the absence of the designer receptors) ( Mahler & Aston-Jones, 2018 ). In this review, we focused on modern tools to manipulate neural circuits, but there are increasing attempts to integrate these neural-control tools with techniques for monitoring neural activity and tagging activated cells, such as Ca 2+ imaging and neural tagging to reactivate specific populations of cells that were previously activated ( Carrillo-Reid, Yang, Kang Miller, Peterka, & Yuste, 2017; Liu et al., 2012 ). For integrating optogenetics with Ca 2+ imaging, opsins should be carefully selected, and fluorescent light intensity and wavelength sensitive of the opsin should be tightly titrated to avoid cross-stimulation of opsins by fluorescent light during Ca 2+ imaging. For example, fluorescent light for Green Fluorescent-Calmodulin Protein (GCaMP) imaging can partially activate blue-shifted opsins and also red-shifted opsins. Integrating chemogenetics with Ca 2+ imaging is an alternative option albeit with limited spatiotemporal advantages, but future generations of engineered opsins and Ca 2+ sensors will likely resolve these issues. Recently engineered concurrent detection of elevated calcium and light in a living cell will lead to the development of new tools to “tag” specific populations of cells activated within a specific time window, which would allow the targeted neurons to be controlled by optogenetics or chemogenetics at a later time point ( Wang et al., 2017 ). This tagging technique can be useful in developmental studies to track certain populations of cells tagged in an early stage of development and then investigate their function in later life. For instance, a certain population of neural ensembles that are activated by early life stress/traumatic event can be re-activated or inhibited to test if that particular ensemble is involved in shaping neurodevelopmental disorders (e.g. SSD, ASD, PTSD) ( Kerns, Newschaffer, & Berkowitz, 2015; Schäfer et al., 2012 ). As described above, the recent findings using these new tools provides evidence of the functional relevance of brain circuitry to disease, but some studies have even demonstrated functional rescue in mutant mice. These findings underpin the potential utility of optogenetics and chemogenetics as potentially useful for developing therapeutic applications in human patients ( Gilbert, Harris, & Kapsa, 2014 ). However, there are some considerations and challenges which must be addressed before moving into human applications. First, these techniques are still highly invasive medical procedures. It would be challenging to express opsins or designer receptor genes into adult human neurons within a specific brain area, given the known limitations of gene therapy. In particular, for optogenetic application, effective large fiber optics would have to be designed on a human scale with a sufficient light source. The recent progress in developing wireless options using miniaturized, thin, flexible optoelectronic implants is a promising advance ( Shin et al., 2017 ). The other issue regarding human application of these tools is that most current neural circuitry studies apply optogenetic and chemogenetic tools for acute treatment. These techniques are still poorly understood in terms of their stability and impact following chronic stimulation and/or long term expression in cells and neurons. For instance, there is a lack of information regarding cellular health with long-term virus expression or chronic repeated photo- or chemical activation of neurons. There will certainly be further technological advancement in optogenetics and chemogenetics as the National Institutes of Health and National Science Foundation BRAIN initiatives continue to invest in new tools for dissecting brain function; undoubtedly this will lend several new tools for exploring psychiatric dysfunction. Lastly, in parallel with technological developments to control neural circuits, systematic evaluation of behavioral tests is of great importance in making careful interpretations and conclusions with results of optogenetic and chemogenetic circuit manipulations. Although the contemporary tools that we have discussed above offer a highly sophisticated approach to controlling neural circuits, the way the field translates the function of a circuit is ultimately based on outcomes of behavioral changes. Unfortunately, most behavioral tests have an inherent complexity (i.e. multiple cognitive/motivational factors could affect a single behavior test), and it can be difficult to draw a clear conclusion with a simple behavior test and measurement in rodents. For example, as we discussed above, most literature in this field uses rodent social interaction tests controlling a targeted-circuit, to claim that the targeted-circuit is involved in social dysfunction that is a common phenotype of many psychiatric disorders including ASD and SSD ( Cho & Sohal, 2014; Krishnan et al., 2017; Yizhar et al., 2011 ). In the standard social interaction test, animals explore a chamber where conspecific animals are constrained under a mashed cup, and their exploration time with the constrained mice is measured. However, human social behavior is much more complex, and measuring exploration time, even without contacts between animals in the test, provides only limited insights into social behavior ( Hånell & Marklund, 2014 ). That is, it is not clear if the circuit manipulation affected only the recognition/memory of a conspecific animal or changed their social interest/communication within the measurement. Measuring a complimentary rich suite of other social behaviors such as sniffing, playing, and ultrasonic vocalization would help make a stronger interpretations of the circuit manipulation and assist in finding adequate matches to known phenotypic traits of psychiatric disorders. Also, it is often important to test behaviors combining optogenetic and chemogenetic controls with etiologically relevant pharmacological treatment. For example, in the OCD study mentioned above, Ahmari et al. (2013) showed that cortico-striatal optogenetic stimulation increased self-grooming behavior. However, it may not necessarily implicate an emotion-related circuit mechanism of OCD (i.e. it could be just increment of motor function related to the pattern of grooming behavior). In the study, the authors showed that the excessive grooming behavior evoked by optogenetic stimulation was reversed by chronic fluoxetine treatment that is used as a first-line OCD treatment. Therefore, rigorous behavioral testis using parallel classical and contemporary neural control tools are demanded. Also, it is important to continue developing additional behavioral models that more realistically reflect clinical behavioral traits; and further developments in machine – learning to measure behavioral outcomes in non-biased ways are at the forefront of some of this research ( Wiltschko et al., 2015 ). 5 Funding Information: We thank Skylar M. Spangler for comments on the manuscript. This work was supported by National Institute of Health Grants: NIH R01MH112355, and BRAIN Initiative 1U01 MH109133. Publisher Copyright: © 2018 Elsevier Inc.

PY - 2019/11

Y1 - 2019/11

N2 - Great efforts in clinical and basic research have shown progress in understanding the neurobiological mechanisms of neurodevelopmental disorders, such as autism, schizophrenia, and attention-deficit hyperactive disorders. Literature on this field have suggested that these disorders are affected by the complex interaction of genetic, biological, psychosocial and environmental risk factors. However, this complexity of interplaying risk factors during neurodevelopment has prevented a complete understanding of the causes of those neuropsychiatric symptoms. Recently, with advances in modern high-resolution neuroscience methods, the neural circuitry analysis approach has provided new solutions for understanding the causal relationship between dysfunction of a neural circuit and behavioral alteration in neurodevelopmental disorders. In this review we will discuss recent progress in developing novel optogenetic and chemogenetic strategies to investigate neurodevelopmental disorders.

AB - Great efforts in clinical and basic research have shown progress in understanding the neurobiological mechanisms of neurodevelopmental disorders, such as autism, schizophrenia, and attention-deficit hyperactive disorders. Literature on this field have suggested that these disorders are affected by the complex interaction of genetic, biological, psychosocial and environmental risk factors. However, this complexity of interplaying risk factors during neurodevelopment has prevented a complete understanding of the causes of those neuropsychiatric symptoms. Recently, with advances in modern high-resolution neuroscience methods, the neural circuitry analysis approach has provided new solutions for understanding the causal relationship between dysfunction of a neural circuit and behavioral alteration in neurodevelopmental disorders. In this review we will discuss recent progress in developing novel optogenetic and chemogenetic strategies to investigate neurodevelopmental disorders.

KW - Autism

KW - Chemogenetics

KW - IDD

KW - Neurodevelopment

KW - Optogenetics

KW - Schizophrenia

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U2 - 10.1016/j.nlm.2018.03.015

DO - 10.1016/j.nlm.2018.03.015

M3 - Article

C2 - 29550367

AN - SCOPUS:85044311063

SN - 1074-7427

VL - 165

JO - Neurobiology of Learning and Memory

JF - Neurobiology of Learning and Memory

M1 - 106835

ER -

Contemporary strategies for dissecting the neuronal basis of neurodevelopmental disorders

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