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Local and long-range input balance: A framework for investigating frontal cognitive circuit maturation in health and disease
Local and long-range input balance during frontal cortex development
https://orcid.org/0000-0003-2478-1721
Allen Samuel J. Conceptualization Visualization Writing - original draft Writing - review & editing 1 2 3 4 5
https://orcid.org/0000-0002-1045-1337
Morishita Hirofumi Conceptualization Funding acquisition Project administration Supervision Visualization Writing - review & editing 1 2 3 4 5 *
1 Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
2 Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
3 Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
4 Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
5 Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
* Corresponding author. Email: hirofumi.morishita@mssm.edu
20 9 2024
18 9 2024
10 38 eadh392031 1 2024
12 8 2024
Copyright © 2024 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
2024
The Authors
https://creativecommons.org/licenses/by-nc/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

Frontal cortical circuits undergo prolonged maturation across childhood and adolescence; however, it remains unknown what specific changes are occurring at the circuit level to establish adult cognitive function. With the recent advent of circuit dissection techniques, it is now feasible to examine circuit-specific changes in connectivity, activity, and function in animal models. Here, we propose that the balance of local and long-range inputs onto frontal cognitive circuits is an understudied metric of circuit maturation. This review highlights research on a frontal-sensory attention circuit that undergoes refinement of local/long-range connectivity, regulated by circuit activity and neuromodulatory signaling, and evaluates how this process may occur generally in the frontal cortex to support adult cognitive behavior. Notably, this balance can be bidirectionally disrupted through various mechanisms relevant to psychiatric disorders. Pharmacological or environmental interventions to normalize or reset the local and long-range balance could hold great therapeutic promise to prevent or rescue cognitive deficits.

The development of local and long-range inputs onto frontal circuits is understudied and can be used to reduce cognitive deficits.

http://dx.doi.org/10.13039/100000002 National Institutes of Health R21NS105119, R21MH106919, R01MH119523, R01EY031009, RF1AG085887, T32MH135853 http://dx.doi.org/10.13039/100000002 National Institutes of Health T32MH135853 http://dx.doi.org/10.13039/100000297 FRAXA Research Foundation NA http://dx.doi.org/10.13039/100014370 Simons Foundation Autism Research Initiative 977966
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pmcINTRODUCTION

Human brain maturation is a lengthy and complex process that spans the first 2 decades of life (1). As the brain develops through childhood and adolescence, more complex and cognitively demanding behaviors begin to arise (2). Notably, many psychiatric disorders, such as autism spectrum disorder (ASD) and schizophrenia, also start to display symptoms along a similar timeline in development (3–5). This phenomenon is likely a reflection of pathological impacts during development as circuits are refined for adult behavior functioning. During this period of maturation, circuits are malleable to influences from genetic and environmental factors, which may alter circuit development trajectory. It is thus crucial for psychiatric disorder research to investigate circuit maturation and to provide developmental context when evaluating new treatment approaches.

In regard to psychiatric disorders, the frontal cortex has long been positioned as an area of interest given that deficits in executive functioning are characteristic of these disorders (6). Notably, the frontal cortex is one of the last brain regions to develop, which further highlights the complex developmental processes underlying behavior maturation (7). However, this prolonged development is also a period of increased risk for psychopathologies (8, 9). The frontal cortex undergoes an increase in synapse number followed by a gradual decrease until reaching stability into adulthood (10, 11). Examination of dendritic spine density in frontal cortex from postmortem human tissue found that layer IIIc pyramidal neurons reach peak density around years 2.5 to 7 while layer V pyramidal neurons reached their peak later at around 7 to 9 years (12). Following this increase, synaptic density in human prefrontal layer IIIc pyramidal neurons decreases, with the loss becoming significant by age 17 and reaching adult levels by around age 30 (12). Rodents also display a similar rise in synaptic and spine density in the frontal cortex, peaking around postnatal day 30 (p30), followed by a reduction during the transition from adolescence to adulthood (13–18). This developmental change is reflective of circuits producing and then refining connections to other neurons (19–21). Notably, changes in these developmental processes have been observed in postmortem brains diagnosed with ASD and schizophrenia and in related animal models (22–27).

While these findings are intriguing, they lack the larger context of what specific changes are occurring at the specific circuit level. Frontal cortex circuitry has been particularly difficult to study because the area makes a vast number of heterogeneous connections between multiple sensory cortexes and subcortical regions to produce complex cognitive behaviors (28–32). Understanding how frontal circuits regulate and refine their connections during development could provide insight into how these maturation processes are disrupted in neuropsychiatric disorders and could put forth promising therapeutic targets and intervention windows. Until recently, investigating individual inputs and outputs of circuits has not been feasible, but with the invention of circuit-selective techniques such as rabies virus–based monosynaptic input mapping, optogenetics, chemogenetics, circuit-specific input evaluation, and fiber photometry, circuit connectivity and activity can now be directly associated with behavioral function (33–35). These circuit-selective techniques have made it possible to investigate circuits with complex connectivity patterns that could be relevant to disorder pathology.

In this review, we will highlight research examining how connectivity of frontal circuits changes during development. Specifically, we will focus on how inputs from local neurons and from long-range circuits are refined during postnatal maturation, when synaptic density declines, and in the context of neuropsychiatric disorders. Because of the wide variation in frontal circuitry and the limited developmental studies that directly link local/long-range input balance and behavioral function, this review will use one type of frontal circuit in mice (top-down frontal-visual cortico-cortical projection neurons) as an example throughout this review as their causal behavioral role and maturation process at the level of local and long-range inputs are both characterized (36–39). First, we will highlight how the balance of local/long-range inputs progresses across development and discuss possible mechanisms underlying connectivity maturation. Next, we will provide examples of how this balance may become dysregulated by risk factors of neuropsychiatric disorders. Last, we will evaluate how changes in local/long-range balance are relevant for therapeutic development and provide future avenues for how these findings can be used to design more effective interventions.

LOCAL/LONG-RANGE BALANCE SHIFT: AN EMERGING FRAMEWORK FROM STUDIES OF FRONTAL-VISUAL CORTICAL NEURONS IN MICE

During early development when frontal cortex synaptic density is rising, local inputs between neighboring neurons increase as well as long-range inputs as stereotypic projections from other cortical and subcortical regions are established (40). For example, long-range inputs from the amygdala, hippocampus, and ventromedial thalamus all reach the frontal cortex within the first 3 weeks of postnatal development in mice (41, 42). However, while many studies have broadly determined the sources of inputs to and within the frontal cortex during the developmental rise in synaptic density, little is known about how these inputs are selectively refined at the individual circuit level when synaptic density decreases. The amounts and types of local and long-range inputs onto frontal cortex neurons are highly variable between different layers and individual neurons (29). Furthermore, how refinement of local and long-range inputs during later postnatal development promotes adult cognitive functioning is unclear. To most effectively highlight how the development of local and long-range inputs relates to behavior function, this review will use research on mouse frontal-visual cortical neurons projecting from anterior cingulate area (ACA) to visual cortex as an example circuit. We chose this circuit because it has recently been shown to be casually responsible for top-down sensory modulation (36, 37, 39), including performance improvement following error trials during sustained attention tasks (38). In addition, the local and long-range input connectivity of this circuit has been evaluated across postnatal development (14, 15). Development of top-down cortical propagation is also increasingly being recognized as a key signature of cognitive maturation in human (43). Given these findings, this example circuit provides a framework for linking the changes in local/long-range input connectivity with cognitive behavioral maturation.

Local/long-range balance shift across adolescence

Frontal-visual cortical neurons undergo notable postnatal developmental changes of their input connectivity. These neurons display a significant increase in the density of mature mushroom dendritic spines following adolescence (p33) into adulthood (p81), while immature thin spines show a nonsignificant trending decrease (15). At the functional level, these neurons show a higher excitatory drive during early adolescence (p29 to p37) compared to adulthood (p65 to p110) (14). Moreover, this increased excitatory drive was found to be essential for the establishment of attentional behavior in adulthood (14). On the other hand, inhibitory drive onto frontal-visual cortical neurons was found to be relatively stable over development (14). The field of circuit research has widely referred to the balance between excitatory and inhibitory drives (E/I) when characterizing circuit dynamics (44, 45). While this measure has provided tremendously useful insight into circuit function, E/I balance has not been able to fully explain observed circuit phenomena (46). Here, we will focus on the connectivity balance between excitatory local and long-range inputs onto frontal circuits during development. In this review, we refer to inputs from neighboring neurons within the same cortical areas as local, and inputs from other cortical or subcortical distal brain regions as long-range.

This increased excitatory drive onto frontal-visual cortical neurons during early adolescence was further characterized using monosynaptic rabies input tracing in both adolescent (p38) and adult mice (p84) (14). Local inputs from the ACA and the neighboring secondary motor cortex, where the frontal-visual cortical neurons are located, decrease from adolescence to adulthood. Long-range inputs from other brain regions remain stable across the same developmental window. These experimental approaches do not distinguish whether the increase in local input drive is due to an increase in synaptic release, synaptic contacts, axon collaterals, or number of neurons connected; future studies are required to parse these events. While only local inputs were found to be altered in this study, this finding demonstrates that the pruning mechanisms underlying this maturation are able to selectively eliminate local inputs while preserving long-range inputs. Moreover, as local inputs tend to preferentially target proximal dendrites (47), removal of irrelevant local inputs may promote somatic transmission from long-range inputs targeting distal dendrites. In this way, the reduction in local inputs may more efficiently increase the functional contribution of long-range inputs without the need for rewiring long-range connectivity (48–50). These findings raise a possibility that frontal-visual cortical circuit maturation is accomplished during adolescence—in part—by fine-tuning the balance of local and long-range inputs as local inputs are eliminated.

Contribution of early adolescent neural activity on local/long-range balance

To understand to what extent this transient early adolescent stage of increased local inputs and frontal-visual cortical neuron activity affect adult function, the study further examined how suppression of neural activity during early adolescence affected its maturation (14). The chemogenetic suppression of frontal-visual cortical neuron activity during early adolescence (p25 to p35) resulted in reduced attention-task performance in adulthood. Moreover, electrophysiological assessment revealed excessively reduced local excitatory inputs compared to adult controls and reduced spine density selectively at proximal dendrites—where local inputs are enriched—in the early adolescent suppressed group (14). In contrast, chemogenetic suppression during young adulthood (p45 to p55) did not reproduce these deficits, indicating early adolescence as a sensitive period for activity-dependent maturation (Fig. 1A) (14). These findings point to early adolescent neural activity as one of the key regulators of local input maintenance. This study did not evaluate the effects of the chemogenetic suppression on long-range inputs, and more research is needed to directly examine the changes, if any, of long-range inputs. However, since only the spine density of the proximal dendrites, where local inputs preferentially target (47), decreased in the adolescent suppressed group, it appears that developmental suppression of the circuit preferentially reduces local inputs while sparing long-range inputs. One explanation for this observation could be that the reduced local inputs are from neighboring frontal-visual cortical neurons, which would mean that both the postsynaptic neuron and presynaptic input activities are suppressed.

Fig. 1. Developmental refinement of local/long-range inputs onto frontal circuits.

(A) An example circuit (frontal-visual cortical neuron) shows a change in the ratio of local and long-range inputs during postnatal development. (Top) Local inputs (blue) from neighboring neurons decreased relative to long-range inputs (red) from other brain regions. This refinement of inputs requires Lynx1 (green): an endogenous suppressor of nicotinic signaling. (Bottom) In the same neuronal population, the balance of local/long-range inputs shifts across development. Early and late adolescence are developmental windows when circuit activity and neuromodulatory changes respectively can affect local/long-range input balance; however, as the circuit matures into young adulthood, circuit activity is no longer able to cause sustained change. (B) Changes in the balance of local/long-range inputs occurs in parallel with other maturational processes in the frontal cortex including changes in synaptic density, nonneuronal factors (microglia-mediated pruning and myelinogenesis), and neurmoduatory factors (5-HT, cholinergic, and dopaminergic). While these broader developmental processes in the frontal cortex have been studied extensively, future studies are warranted to examine their specific contributions on regulating the balance of local and long-range inputs.

While these findings demonstrate that changes in local and long-range connectivity can have lasting effects on the development of cognitive functions, it remains unclear how these inputs are selected for modification at the individual circuit level during postnatal maturation. Examining other developmental processes that are occurring during the same time frame as local/long-range input refinement may provide clues for answering this question in future studies. One candidate process is microglia-mediated pruning of synapses during postnatal development. Recently, microglia have been positioned as prominent regulators of circuit connectivity and maturation through removal of synapses (51). One study found that adolescent—but not adulthood—ablation of microglia activity resulted in altered frontal network activity, cognitive impairment, and morphological changes of spine density in layer 2/3 pyramidal neurons (13). In addition, microglia have been found to sense and respond to neuronal activity (52, 53), which may provide an explanation for how altered activity during development leads to disrupted local/long-range balance and cognitive deficits. However, these studies do not provide insight into the inputs, at the circuit level, that are removed by microglia leading to cognitive deficits.

Another developmental process that may help to explain the selective refinement of local and long-range inputs is developmental changes in myelination. Myelination of axon fibers allows for faster neuronal communication and continues to mature from early postnatal development into adulthood (54). Myelination is known to play an important role in modifying axon transmission properties and regulating communication between distal brain regions (55); moreover, myelin structure has been shown to be remodeled during motor learning (56). Myelination has been shown to be promoted by neuronal activity, which may provide selectivity for enhancing certain inputs during circuit maturation (57, 58). While these findings for both microglia pruning and myelination do not directly examine their effects on local/long-range input balance, they do provide research avenues for furthering the field’s understanding of the mechanisms mediating frontal circuit connectivity maturation (Fig. 1B). On the basis of these results, it is possible that molecular differences between local and long-range inputs may mediate their removal via microglia or their preservation through myelination; however, more work is needed to understand the pathways involved in guiding these processes during postnatal development.

Role of neuromodulatory system on local/long-range balance shift

In parallel to changes in synapse turnover and connectivity, neuromodulatory systems are also developing during this maturation window. The main neuromodulatory systems—dopamine, serotonin (5-HT), acetylcholine (ACh), and norephedrine—are known to innervate the frontal cortex and are involved in various cognitive, emotional, and social behaviors (15, 59–63). Innervation of the frontal cortex by these systems occurs across various windows during postnatal development. For example, cholinergic projections from basal forebrain reach adult levels of innervation in rats by p32 (64). Dopaminergic projections do not reach adult levels of frontal innervation in rats until p60 (65).

If neuromodulatory systems are providing input to the frontal cortex during development, could they play a role in shaping the input connectivity of frontal circuits? Further work in the example frontal-visual cortical circuit suggests that ACh signaling is involved in selective refinement of local inputs. Recent investigations of ACh signaling have shown that there are projections from the basal forebrain onto frontal-visual cortical neurons (15, 63). Previous studies have shown that nicotinic signaling is tightly balanced through a multilayered set of mechanisms across early development: regulation of developing cortex through fetal choline level (66), cholinergic innervation from basal forebrain (67), and the expression level of nAChRs (68) during the first three postnatal weeks in rodents (69, 70). However, it is not clear to what extent cholinergic signaling contributes to the input refinement of frontal circuits in later stages of postnatal development, specifically adolescence.

As stated earlier, frontal-visual cortical neurons undergo a shift in local/long-range balance during maturation as local inputs are eliminated. Further electrophysiological evaluation of these neurons revealed that the circuit’s nicotinic tone is relatively higher in early adolescence (p34), which is then suppressed as the circuit matured into adulthood (p77) (15). This suppression was noted to happen in the same time frame as Lynx1—a known nicotinic tone suppressor and plasticity regulator—expression increased (71, 72). Notably, an examination of frontal-visual cortical neurons in adult Lynx1 KO mice showed early adolescent-reminiscent increased excitatory input, mainly driven by increased local input onto the neurons (Fig. 1A) (15). Expectedly, knockout of Lynx1 in frontal-visual cortical neurons from adolescence also led to dysregulated attentional behavior in adulthood (15). These findings establish a key a role of Lynx1 in adolescent frontal cortical maturation, extending the previously reported role of Lynx1 in limiting developmental cortical plasticity in sensory cortices (71, 73–75). These results demonstrate an importance of regulating ACh signaling in shifting the balance of local and long-range inputs during late adolescent circuit maturation and provide an example of how neuromodulatory signaling may regulate specific circuit developmental processes (Fig. 1A).

These findings are only for an individual circuit; future research is needed to understand how this neuromodulatory-mediated input refinement differs in other cognitive circuits. In addition, while no other studies have examined how other neuromodulatory systems affect local and long-range inputs, there is evidence that these systems play a role in connectivity maturation across postnatal development. For example, 5-HT signaling is known to play an early role in frontal postnatal development. During the first 2 weeks of postnatal development in mice, 5-HT signaling increases density and strength of excitatory synapses in the frontal cortex (76), and alterations in its signaling during this time frame can lead to impaired frontal functioning in adulthood (77). While 5-HT signaling has a role during early brain development, other neuromodulatory systems could be playing a role during later adolescent development when frontal circuit refinement is occurring. One enticing candidate could be dopamine signaling (Fig. 1B). Dopaminergic projections from mesolimbic nuclei continue to arrive and innervate the frontal cortex throughout adolescence (78–80). Dopaminergic signaling has been implicated in the shaping and retraction of neurites in cultured neurons (81, 82). Moreover, dopaminergic signaling through the D1 and D2 receptor in frontal cortex can modulate synaptic plasticity, which could affect how inputs are refined during increased synapse elimination in late postnatal development (83, 84).

All of these findings demonstrate that neuormodulatory systems play a broad role in regulating synaptic function and connectivity during postnatal development; however, future research at the level of individual cognitive circuits is needed to understand how these systems refine specific inputs for future cognitive functioning. A potential starting point could be to examine the expression of receptors for neuromodulatory systems in frontal circuits and their inputs during developmental refinement as their expression is known to be highly diverse spatially, temporally, and functionally in the frontal cortex (68, 80, 85–89). Understanding how neuromodulatory systems modulate individual inputs onto frontal circuits during postnatal development will provide insight into the mechanisms that shape local and long-range inputs for future cognitive functioning and could provide avenues for investigating how this development may be perturbed in neuropsychiatric disorders.

Possible link between activity sensitive period and neuromodulatory system

As discussed above, research on the example frontal-visual projection circuit has demonstrated developmental windows where changes in activity or neuromodulatory signaling can alter local/long-range input balance and subsequent cognitive behavior. Notably, the sensitive period of activity-dependent refinement of local-inputs (14) closes when a suppression of nACh signaling occurs by increased expression of Lynx1. The sequence of these developmental events raises an intriguing possibility that the Lynx1 increase in frontal-visual cortical neurons contribute to the closure of this activity-dependent sensitive period. This idea is supported by research in the visual cortex that found that increasing Lynx1 expression in adulthood limits neuronal plasticity (71). On the basis of these findings, neuromodulatory systems may be responsible for regulating the developmental window when circuit activity can modify inputs. In addition, neuromodulatory signaling could also influence circuit activity during input refinement. Neuromodulatory signaling—especially cholingeric, noradernrgic, and dopaminergic—in the frontal cortex has been repeatedly demonstrated to be essential for modulating cognitive behaviors in adulthood (90–92). Given that these systems are integral in modifying frontal circuits’ activity during cognitive functioning, it could be hypothesized that early neuromodulatory signaling during developmental refinement of circuit inputs helps to distinguish which inputs are eliminated or preserved in an activity-dependent manner for future cognitive function. Future research is needed to understand the interplay between circuit activity and neuromodulation in refining frontal circuit connectivity during development.

LOCAL/LONG-RANGE IMBALANCE AND PSYCHIATRIC DISORDERS

The previous sections demonstrate that the ratio of local and long-range inputs can shift while circuit maturation occurs during postnatal development. In addition, studies on the example frontal-visual cortical circuit suggest that neural activity and neuromodulatory signaling are key regulators of local/long-range input ratio across development. Given that this developmental shift is important for the circuit’s function and behavior production, understanding how this maturation is affected in the context of psychiatric disorders may help to explain how behavior deficits are produced at the circuit level. Because these disorders are known to have developmental origins, the influences of genetic and environmental factors may converge on circuits during local/long-range input refinement, leading to later circuit dysfunction. A multitude of studies have demonstrated general connectivity differences in cortical areas in both autism and schizophrenia (93–96). Moreover, developmental processes that can alter circuit connectivity have been found to be perturbed in psychiatric disorders. For example, synapse pruning is known to be disrupted in both schizophrenia and autism, potentially underlying observed differences in synaptic density (97–99). Unbiased genome-wide studies also support the genetic contribution of synaptic and axon guidance pathway genes for autism and schizophrenia risk (100–102). In addition, studies have found deficits in neuromodulatory signaling in psychiatric disorders, which—on the basis of the findings in the section “Role of neuromodulatory system on local/long-range balance shift”—may be involved in the observed altered connectivity (103–105). Given that these processes can affect circuit connectivity, it follows that their disruption could affect the balance of local and long-ranged inputs onto cortical neurons, leading to the precipitation of cognitive deficits. In principle, the ratio of local/long-range inputs can be shifted high or low through different mechanisms (Fig. 2). As both high and low local/long-range ratio are associated with cognitive deficits in the example circuit from the section “Local/long-range balance shift across adolescence” (14, 15), the balance of the local/long-range input ratio within a certain range may be essential for the establishment of proper cognition. In this section, we will summarize findings that suggest how disorder processes can influence local/long-range balance.

Fig. 2. Dysregulated local/long-range balance by risk factors of psychiatric disorders.

(Middle) Typical circuit maturation is marked by the circuit reaching a specific balance between local and long-range inputs, which is able to produce appropriate behavior. (Left) High local/long-range balance can be produced from increased local inputs or decreased long-range inputs, which leads to behavior deficits; such disturbances can be caused by genetic mutations and environmental exposure. (Right) Low local/long-range balance can occur through increased long-range inputs or decreased local inputs through genetic mutations and reduced cortex activity, also leading to behavior deficits.

High local/long-range ratio

In human studies, ASD has been known to be associated with reduced long-range functional connectivity across the brain (106, 107). However, it has recently become evident through functional magnetic resonance imaging (fMRI) studies that alterations of local connectivity are also involved in perturbed ASD connectivity, especially across development (108–113). These findings point to a shift in ASD of local/long-range input balance to a hyperlocal state. While these findings are promising, the noninvasive imaging methods used can only provide a broad understanding of functional connectivity imbalance. To build on this research, rodent studies are an essential step to more precisely determine the changes occurring at the circuit level.

Returning to the previously used example of the top-down frontal-visual cortical circuit from the section “Local/long-range balance shift across adolescence,” follow-up analysis revealed that adult Fmr1 KO mice [a mouse model of Fragile X syndrome (FXS)] have increased nicotinic signaling and hyperlocal connectivity in frontal-visual cortical neurons and accompanied attention deficits in adulthood (Fig. 2) (15). These results may reflect immature hyperlocal connectivity that is not reduced following adolescence, consistent with previous studies that have found that Fragile X Messenger Ribonucleoprotein 1 (the protein deficient in FXS) promotes synaptic pruning (114). In addition to hyperlocal connectivity, a recent study showed that postsynaptic deletion of Fmr1 in layer V cortical neurons resulted in reduced long-range callosal synapses (115), suggesting that reduction of long-range inputs can additionally drive the shift to a higher local/long-range balance (Fig. 2). Of note, postsynaptic deletion of Fmr1 in layer II/III neurons did not affect local inputs, suggesting that different cortical layers and cell populations can have diverse changes in local/long-range balance in disease states (115–117). Moreover, these findings using Fmr1 manipulation show that a single genetic perturbation can affect both local and long-range inputs in different directions. Increased local/long-range input balance has also been implicated in pathology associated with ASD-related environmental factors. The starkest example is that of the antiepileptic drug valproate acid (VPA). Multiple studies have shown that VPA taken during neural tube closure in early prenatal development can greatly increase the risk of autism (118–121). Notably, rats exposed to VPA prenatally have shown a higher number of local connections in the somatosensory cortex (122) and the frontal cortex (Fig. 2) (122). Future studies are needed to generalize these findings to other mouse models and environmental factors.

Low local/long-range ratio

On the other side of the spectrum, reduced local/long-range balance may also cause disruptions in circuit development and function. As mentioned earlier, chemogenetic suppression of the example frontal-visual cortical circuit’s activity in mice during early adolescence (p25 to p34), but not young adulthood (p45 to p54), leads to dysregulated cognitive behavior in adulthood accompanied by excessive reduction of local inputs (14). In addition to frontal-visual cortical projection neurons, recent studies also took similar approaches to chemogenetically suppress the activity of major input sources to the frontal pyramidal neurons selectively during adolescence to demonstrate that there is an adolescent sensitive period when circuit activity is essential to establish proper cognitive behavior and frontal connectivity in adulthood (123, 124). These findings highlight how circuit activity can play a role in balancing local and long-range inputs during development (Fig. 2). Notably, recent studies showed that the deletion of microglia during adolescence but not in adulthood also leads to long-lasting frontal cortical synaptic deficits and cognitive deficits (13, 51). Given that the microglia are known to monitor and regulate neural activity (52, 53, 125), it raises the possibility that microglia mediate the neural activity-dependent control of local/long-range input balance in frontal cortex, which warrants future investigations.

Environmental risk factors for psychiatric disorders have also been proposed to affect brain development and circuit function (126, 127). One such example is that of cannabis use during adolescence, which has been widely associated with increased risk of psychiatric disorders, especially schizophrenia (128). Cannabis use during adolescence has also been shown to reduce prefrontal cortex activity in fMRI studies (129). Similarly, high levels of alcohol consumption during adolescence have reportedly been associated with cognitive deficits in adulthood (130). Acutely, alcohol consumption is known to reduce prefrontal cortex activity (131). Moreover, mouse models of adolescent binge drinking displayed reduced intrinsic excitability in prefrontal cortex neurons (132). Given that the chemogenetic suppression of frontal circuit activity during early adolescence causes adult cognitive deficits in mice (14, 124), these external factors that affect cortical activity during early adolescent sensitive periods may also lead to impaired cognitive functioning that persist until adulthood. Since experience and circuit activity are known to play a role in synapse pruning (22, 133), we hypothesize that suppression of frontal cortical activity during early adolescence may reduce local input activity leading to decreased local/long-range input balance.

Exposure to substances that can alter circuit development is not limited to those that affect only circuit activity; they can also affect neuromodulatory systems, which are another key candidate for regulating local/long-range input balance. For example, cocaine exposure—which acts on the dopaminergic system—during adolescence (p28 to p42) in rats has been shown to impair attention performance and reduce frontal cortical synaptic density in adulthood (134). Moreover, substance exposure can also directly alter the development of neuromodulatory systems, which may have lasting effects on subsequent circuit refinement. Recreational use of amphetamines during adolescence has been shown to disrupt the netrin-1/DCC guidance of dopamine inputs initially bound for the nucleus accumbens causing them to instead innervate the frontal cortex in mice (135). Furthermore, genetic disruption of the same guidance system led to similar misguided dopamine innervation to the frontal cortex, reduced dendritic spine density, and fewer basal dendritic branches in frontal pyramidal neurons (136). These findings demonstrate that exposure to substances during development can disrupt the maturation of neuromodulatory signaling and lead to sustained changes in frontal cortical neuron dendritic spines. While more research is needed to understand how exposure to these substances during development affects individual circuit connectivity, these findings provide a starting point in linking the effects of environmental factors that disrupt local/long-range input balance with subsequent cognitive deficits in adulthood. Moreover, given that the time period from late childhood to adolescence—when frontal circuit refinement occurs—is often when individuals are exposed to many of these factors, research on the mechanisms underlying their effects on circuit input balancing could have tremendous impact on pediatric treatment.

Genetic risks of neurodevelopmental disorders are also linked to reduced local/long-range input balance. Myocyte Enhancer Factor 2C (Mef2c) mutations have been associated with intellectual disability syndromes and ASD, while the Mef2c locus is associated with risk for schizophrenia and ASD (137, 138). Mef2c is a transcription factor that has been shown to regulate synapse density (139–141). A recent study that examined the impact of postnatal postsynaptic deletion of Mef2c in layer II/III pyramidal neurons found that Mef2c deletion leads to hypo-local excitatory inputs and excessive callosal long-range excitatory inputs (Fig. 2) (142). These effects were prevented by sensory deprivation via whisker trimming. This finding highlights how circuit development pathways can be dependent on experience and how multiple factors play a role in shaping local/long-range balance. Of note, schizophrenia is characterized by reduced spine density in various cortical areas (26, 143, 144). Consistently, reduced spine density and dendritic complexity in frontal cortical neurons have been observed in the context of 15q13.3 microdeletion (145), one of the major copy number variations associated with schizophrenia and other psychiatric conditions. Similarly, overexpression of complement component 4 (C4)—a common risk variant of Schizophrenia (146)—in mice found reduced mature frontal cortex spines and decreased functional connectivity (147). Future studies are warranted to examine to what extent reduced spine density in these models reflects hypolocal inputs and local/long-range balance deficits.

BALANCING LOCAL AND LONG-RANGE INPUTS FOR INTERVENTIONS

While all of these studies have provided intriguing avenues for future research, it remains unclear how these differences in cortical local/long-range balance factor into potential treatment paradigms. Our current medication regimes for psychiatric disorders are severely lacking for disorder course modification and only moderately alleviate symptoms. For example, antipsychotic medications only alleviate a subset of schizophrenia symptoms, and little, if any, medications provide large benefits for ASD symptoms (148–150). Because the overwhelming majority of these medications were developed on the basis of clinical observations, there is little, if any, understanding of how these treatments produce effects at the circuit level to alleviate symptoms. Our current understanding of psychiatric disorders points to intervention during early childhood and adolescence, when the brain is developing, as the likely most effective way to influence disorder course (151–153). Considering the changes in synapse number, function, and connectivity that occur during development, intervention during these shifts may help to support normal development and provide sustained benefits (154, 155). Here, we will highlight the potential avenues, based on current research, for intervening during this developmental period to promote proper balancing of local and long-range connectivity.

Restoring circuit activity during sensitive period

One possible therapeutic approach to promote correct balancing of local/long-range connections is manipulation of circuit activity during developmental sensitive periods (Fig. 3A). Previous results showing chemogenetic suppression of frontal-sensory neuron activity during early adolescence provide evidence to support the idea that activation of circuits at critical time points is necessary for later function of the circuit and for correct balancing of local/long-range inputs (14). It could even be hypothesized that the observed efficacy of behavioral interventions during developmental for ASD is—in part—a result of promoting typical refinement of circuit connectivity by activating cognitive circuitry (156, 157). More recently, transcranial magnetic stimulation treatments have been developed that can noninvasively manipulate network activity and that are already being used for treatment of psychiatric disorders in adults, with growing interest in advancing to pediatric utilization (158, 159). Consistently, animal studies supports the beneficial effects of behavioral intervention and electrical neurostimulation during the adolescent period (154, 155, 160). However, more research needs to be done to understand how manipulation of circuit activity during development promotes long-term changes in circuit dynamics, such as local/long-range balance. Moreover, while we discussed activity manipulation in the context of hypo-local connectivity states, it is theoretically possible to use the activity modulation approach for hyper-local states.

Fig. 3. Potential intervention avenues for correcting local/long-range balance in cortical circuits.

On the basis of the findings in the example frontal-sensory neurons, there are several frameworks for interventional shaping of local/long-range balance that should be investigated. (A) Manipulation of circuit activity during juvenile period could be used to either preserve needed inputs or suppresses unnecessary inputs during maturational synapse pruning. (B) Neuromodulatory intervention using pharmacological treatment could be a viable approach to promoting correct refinement of local/long-range inputs. (C) While circuits are less plastic during adulthood, manipulation of sensitive period regulators to reopen developmental windows could—in theory—allow for activity or neuromodulatory-based intervention to be effective for adult patients.

Restoring developmental dynamics of neuromodulation

Another approach to correct the balance of local/long-range input during development is to make use of the regulators of local/long-range input balance, such as neuromodulatory systems (Fig. 3B). As noted earlier, a shift from high local inputs to lower local inputs during late adolescence is disrupted in a mouse model of Fragile X syndrome leading to prolonged hyper-locality due to a failed suppression of nicotinic signaling (15). Notably, the circuit-selective overexpression of the nicotinic-suppressor Lynx1 from late adolescence in Fmr1 KO mice restored suppression of nicotinic signaling during late adolescence and prevented both the attention deficits and the hyper-local connectivity (15). This finding points to the restoration of neuromodulatory dynamics that are essential for developmental local/long-range balance shift as possible avenues for intervention during circuit development. Given that Lynx1 has been shown to close critical periods for visual cortex and social dominance plasticity (71, 161), this approach can be conceptualized to promote the completion of maturational process by closing the developmental sensitive period when circuits are immature. Notably, in FXS rat model animals, adolescent administration of lovastatin was shown to produce sustained rescue of learning deficits into adulthood (162). Future study is warranted to examine whether this treatment converges with neuromodulatory action and local/long-range rebalancing. While other neuromodulatory systems could—in theory—be used for therapeutic intervention, more research is needed to understand how and when these other systems modify circuit input connectivity. Moreover, while the studies referenced above examined nicotinic signaling in the context of hyper-local connectivity, it is possible that other neuromodulatory signaling pathways could be relevant for hypo-local states.

Reopening of sensitive period for adult intervention

Outside of developmental windows, interventions for adult patients are challenged by the lack of plasticity that may prevent more sustained effects. While some studies have demonstrated rescue of symptoms in mice models of psychiatric disorders through adult intervention (163, 164), the lack of understanding of the adulthood consequences of dysfunctional circuit maturation limits the efficacy and development of treatments. One potential direction for adult treatment would be to combine reopening circuit sensitive periods with circuit activity modulation to allow for acute manipulation of connectivity leading to sustained benefits (Fig. 3C). While circuits are less plastic during adulthood, a combinatorial approach using manipulation of sensitive period regulators to reopen developmental windows and circuit activation to retain relevant inputs could be used for adult patients. For example, manipulation of critical period regulators, such as Lynx1 (71), or valproate treatment can reopen window of plasticity (161, 165) and then can be paired with behavioral training or circuit stimulation to strength relevant connections while removing unnecessary inputs (161). This type of intervention has gained support with the reemergence of interest in psychedelic-assisted psychotherapy for psychiatric disorders (166, 167). Overall, the future research of interventions for psychiatric disorders must begin to focus on developmental circuit dynamics, such as local/long-range balance, to have a more complete view of the mechanisms underlying circuit function and treatment response.

FUTURE DIRECTIONS

All of these studies taken together suggests that local/long-range balance is a key framework to facilitate our understanding of circuit maturation processes, which may be perturbed in psychiatric disorders with developmental etiologies. These results also point to later postnatal development from childhood to adolescence as a window to intervene in balancing of local and long-range inputs to prevent or lessen the development of cognitive deficits. However, much research is still needed to address the gaps in knowledge that are impeding clinical translation.

Given the heterogenous nature of frontal circuits, the mechanisms that refine inputs and the ideal balance between local and long-range inputs likely differ between individual circuits. Moreover, the time course for this developmental refinement of local and long-range inputs could differ between individual circuits. Because of the lack of studies directly examining local/long-range balance in other circuits in the frontal cortex, this review mainly examined local/long-range balance in an example top-down frontal-visual cortical circuit (section “Long-range balance shift: An emerging framework from studies of frontal-visual cortical neurons in mice”). While the various changes in balance observed in the example frontal-visual circuit were mediated by alterations in local inputs, gene mutations (Fmr1 and Mef2C) demonstrated opposing effects between local and long-range inputs. Because studies that provided fragmented and general findings about local and long-range inputs were examined, more research is needed that directly investigates both local and long-range inputs in the same circuit to understand how this balance may differ between frontal circuits. Furthermore, the example circuit used was important for attentional adjustment, but other cognitive processes such as inhibitory control, which is known to show developmental changes (136, 168), should be examined at the circuit level to understand what role input refinement plays in producing functional adult behavior.

Another question that future research should aim to answer is how developmental shifts in local/long-range balance changes the types and proportion of information that is being integrated by the postsynaptic neuron. Because of the complex nature of cognitive tasks, circuits need to receive and compute multiple types of information to produce functional behavior. Local and long-range inputs likely provide varying types of information including sensory information and computations from association cortexes. Elucidating the functional relevance of this shift in local and long-range inputs on frontal circuits during later postnatal development will help to strengthen our understanding of the maturational events underlying the emergence of executive functioning. Future studies that aim to characterize frontal circuit maturation should discern the specific sources of both local and long-range inputs and evaluate how the information provided by these inputs is incorporated into overall circuit function. As circuit-based techniques continue to advance and allow for more precise dissection of frontal circuit properties, newer frameworks—such as local/long-range input balance—will be needed to further our understanding of the relation between development, cognition, and circuit connectivity.

Last, in an effort to produce circuit-based therapeutics, the development of functional biomarkers that can infer local/long-range connectivity will be essential for early treatment interventions. Basic research into how this connectivity shift affects circuit and larger network activity can help guide the development of diagnostic markers. Techniques that can record circuit activity, such as electroencephalogram, are already being used in psychiatric disorders for diagnostic purposes (169–173); however, these technologies are limited by our current understanding of cognitive circuit connectivity dynamics. This gap is even further widened by the lack of knowledge of how circuit connectivity and function mature across development and in disorders with developmental components. The previously discussed research about local/long-range balance is an example of how developmental changes in top-down cognitive circuits can be perturbed in psychiatric disorders leading to disrupted activity and function. As circuit monitoring techniques advance, such disrupted activity could be used as a functional biomarker for local/long-range imbalance. As the search for more effective psychiatric disorder treatments continues, local/long-range balance is an intriguing component of cognitive circuit development that could be a key direction in creating a framework for circuit-based approaches to intervention.

Acknowledgments

Funding: This work was funded by NIH R21NS105119, R21MH106919, R01MH119523, R01EY031009, RF1AG085887, T32MH135853, SFARI (no. 977966), and FRAXA Research Foundation fellowship to H.M. and NIH T32MH135853 to S.J.A.

Author contributions: Conceptualization: S.J.A. and H.M, Supervision: H.M. Writing—original draft: S.J.A. Writing—review and editing: S.J.A. and H.M.

Competing interests: The authors declare that they have no competing interests.

Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper.
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