Neural Circuit Level Research Articles

A historical perspective on the insect central complex: Anatomy, development, and function

The central complex (CX), a remarkable brain region at the core of insect behaviors, has been the subject of extensive research for decades. In this review, we offer a comprehensive historical perspective on the anatomy, development, and function of the CX. The CX consists of discrete and highly structured neuropils found at the center of the brain, which are conserved across insects and arthropods. The developmental processes that shape the CX are themselves conserved across insects. In early research, the CX had been shown to receive visual information and control motor function. Using increasingly advanced methods throughout the years, it has become clear that the CX is involved in high-level behavioral control, such as in vector navigation and goal directed orientation. Its numerical simplicity presents a rare opportunity to study structure-function relationships in small brains, gain insights into evolutionary neurobiology, and develop novel neuromorphic technologies inspired by insect brains. Since the CX is a highly conserved brain region involved in the control of spatial tasks, it is uniquely suited to gain a detailed understanding of the computations required for these processes at the level of neural circuits.

Adenosine-Dependent Arousal Induced by Astrocytes in a Brainstem Circuit.

Astrocytes play a crucial role in regulating sleep-wake behavior. However, how astrocytes govern a specific sleep-arousal circuit remains unknown. Here, the authors show that parafacial zone (PZ) astrocytes responded to sleep-wake cycles with state-differential Ca2+ activity, peaking during transitions from sleep to wakefulness. Using chemogenetic and optogenetic approaches, they find that activating PZ astrocytes elicited and sustained wakefulness by prolonging arousal episodes while impeding transitions from wakefulness to non-rapid eye movement (NREM) sleep. Activation of PZ astrocytes specially induced the elevation of extracellular adenosine through the ATP hydrolysis pathway but not equilibrative nucleoside transporter (ENT) mediated transportation. Strikingly, the rise in adenosine levels induced arousal by activating A1 receptors, suggesting a distinct role for adenosine in the PZ beyond its conventional sleep homeostasis modulation observed in the basal forebrain (BF) and cortex. Moreover, at the circuit level, PZ astrocyte activation induced arousal by suppressing the GABA release from the PZGABA neurons, which promote NREM sleep and project to the parabrachial nucleus (PB). Thus, their study unveils a distinctive arousal-promoting effect of astrocytes within the PZ through extracellular adenosine and elucidates the underlying mechanism at the neural circuit level.

Design of Optogenetic Microimplants for the Treatment of Neurodegenerative Disease

In the context of global aging, neurodegenerative diseases such as Alzheimer’s disease have become important issues in global public health and scientific research. This is due to their soaring incidence, serious impact on patients’ quality of life, and the huge burden they place on families and social economies. However, current treatments, such as drug therapy and deep brain stimulation, have obvious shortcomings. Moreover, there is a lack of precise neuromodulation tools to study the pathogenesis of these diseases In order to solve these problems, optogenetics has attracted attention in recent years, which uses light as a stimulus signal carrier and can realize the detection and control of neurodegenerative diseases at the level of neurons and neural circuits by implanting micro-implants such as μ leds. This review summarize the recent advances in microimplant technology in the fields of optogenetics and neuroscience, and summarize the development and application of optogenetic microimplants for the treatment of neurodegenerative diseases in detail.

Adult neurogenesis is necessary for functional regeneration of a forebrain neural circuit

In adult songbirds, new neurons are born in large numbers in the proliferative ventricular zone in the telencephalon and migrate to the adjacent song control region HVC (acronym used as proper name) [A. Reiner et al., J. Comp. Neurol. 473, 377-414 (2004)]. Many of these new neurons send long axonal projections to the robust nucleus of the arcopallium (RA). The HVC-RA circuit is essential for producing stereotyped learned song. The function of adult neurogenesis in this circuit has not been clear. A previous study suggested that it is important for the production of well-structured songs [R. E. Cohen, M. Macedo-Lima, K. E. Miller, E. A. Brenowitz, J. Neurosci. 36, 8947-8956 (2016)]. We tested this hypothesis by infusing the neuroblast migration inhibitor cyclopamine into HVC of male Gambel's white-crowned sparrows (Zonotrichia leucophrys gambelii) to block seasonal regeneration of the HVC-RA circuit. Decreasing the number of new neurons in HVC prevented both the increase in spontaneous electrical activity of RA neurons and the improved structure of songs that would normally occur as sparrows enter breeding condition. These results show that the incorporation of new neurons into the adult HVC is necessary for the recovery of both electrical activity and song behavior in breeding birds and demonstrate the value of the bird song system as a model for investigating adult neurogenesis at the level of long projection neural circuits.

Serotonergic modulation of vigilance states in zebrafish and mice

Vigilance refers to being alertly watchful or paying sustained attention to avoid potential threats. Animals in vigilance states reduce locomotion and have an enhanced sensitivity to aversive stimuli so as to react quickly to dangers. Here we report that an unconventional 5-HT driven mechanism operating at neural circuit level which shapes the internal state underlying vigilance behavior in zebrafish and male mice. The neural signature of internal vigilance state was characterized by persistent low-frequency high-amplitude neuronal synchrony in zebrafish dorsal pallium and mice prefrontal cortex. The neuronal synchronization underlying vigilance was dependent on intense release of 5-HT induced by persistent activation of either DRN 5-HT neuron or local 5-HT axon terminals in related brain regions via activation of 5-HTR7. Thus, we identify a mechanism of vigilance behavior across species that illustrates the interplay between neuromodulators and neural circuits necessary to shape behavior states.

CRF regulates pain sensation by enhancement of corticoaccumbal excitatory synaptic transmission.

Both peripheral and central corticotropin-releasing factor (CRF) systems have been implicated in regulating pain sensation. However, compared with the peripheral, the mechanisms underlying central CRF system in pain modulation have not yet been elucidated, especially at the neural circuit level. The corticoaccumbal circuit, a structure rich in CRF receptors and CRF-positive neurons, plays an important role in behavioral responses to stressors including nociceptive stimuli. The present study was designed to investigate whether and how CRF signaling in this circuit regulated pain sensation under physiological and pathological pain conditions. Our studies employed the viral tracing and circuit-, and cell-specific electrophysiological methods to label the CRF-containing circuit from the medial prefrontal cortex to the nucleus accumbens shell (mPFCCRF-NAcS) and record its neuronal propriety. Combining optogenetic and chemogenetic manipulation, neuropharmacological methods, and behavioral tests, we were able to precisely manipulate this circuit and depict its role in regulation of pain sensation. The current study found that the CRF signaling in the NAc shell (NAcS), but not NAc core, was necessary and sufficient for the regulation of pain sensation under physiological and pathological pain conditions. This process was involved in the CRF-mediated enhancement of excitatory synaptic transmission in the NAcS. Furthermore, we demonstrated that the mPFCCRF neurons monosynaptically connected with the NAcS neurons. Chronic pain increased the protein level of CRF in NAcS, and then maintained the persistent NAcS neuronal hyperactivity through enhancement of this monosynaptic excitatory connection, and thus sustained chronic pain behavior. These findings reveal a novel cell- and circuit-based mechanistic link between chronic pain and the mPFCCRF → NAcS circuit and provide a potential new therapeutic target for chronic pain.

The mechanistic effects of acupuncture in rodent neurodegenerative disease models: a literature review.

Neurodegenerative diseases refer to a battery of medical conditions that affect the survival and function of neurons in the brain, which are mainly presented with progressive loss of cognitive and/or motor function. Acupuncture showed benign effects in improving neurological deficits, especially on movement and cognitive function impairment. Here, we reviewed the therapeutic mechanisms of acupuncture at the neural circuit level in movement and cognition disorders, summarizing the influence of acupuncture in the dopaminergic system, glutamatergic system, γ-amino butyric acid-ergic (GABAergic) system, serotonergic system, cholinergic system, and glial cells at the circuit and synaptic levels. These findings can provide targets for clinical treatment and perspectives for further studies.

Causal Influence of Linguistic Learning on Perceptual and Conceptual Processing: A Brain-Constrained Deep Neural Network Study of Proper Names and Category Terms.

Language influences cognitive and conceptual processing, but the mechanisms through which such causal effects are realized in the human brain remain unknown. Here, we use a brain-constrained deep neural network model of category formation and symbol learning and analyze the emergent model's internal mechanisms at the neural circuit level. In one set of simulations, the network was presented with similar patterns of neural activity indexing instances of objects and actions belonging to the same categories. Biologically realistic Hebbian learning led to the formation of instance-specific neurons distributed across multiple areas of the network, and, in addition, to cell assembly circuits of "shared" neurons responding to all category instances-the network correlates of conceptual categories. In two separate sets of simulations, the network learned the same patterns together with symbols for individual instances ["proper names" (PN)] or symbols related to classes of instances sharing common features ["category terms" (CT)]. Learning CT remarkably increased the number of shared neurons in the network, thereby making category representations more robust while reducing the number of neurons of instance-specific ones. In contrast, proper name learning prevented a substantial reduction of instance-specific neurons and blocked the overgrowth of category general cells. Representational similarity analysis further confirmed that the neural activity patterns of category instances became more similar to each other after category-term learning, relative to both learning with PN and without any symbols. These network-based mechanisms for concepts, PN, and CT explain why and how symbol learning changes object perception and memory, as revealed by experimental studies.

An Updated Guide to the Identification, Quantitation, and Imaging of the Crustacean Neuropeptidome.

Crustaceans serve as a useful, simplified model for studying peptides and neuromodulation, as they contain numerous neuropeptide homologs to mammals and enable electrophysiological studies at the single-cell and neural circuit levels. Crustaceans contain well-defined neural networks, including the stomatogastric ganglion, oesophageal ganglion, commissural ganglia, and several neuropeptide-rich organs such as the brain, pericardial organs, and sinus glands. As existing mass spectrometry (MS) methods are not readily amenable to neuropeptide studies, there is a great need for optimized sample preparation, data acquisition, and data analysis methods. Herein, we present a general workflow and detailed methods for MS-based neuropeptidomic analysis of crustacean tissue samples and circulating fluids. In conjunction with profiling, quantitation can also be performed with isotopic or isobaric labeling. Information regarding the localization patterns and changes of peptides can be studied via mass spectrometry imaging. Combining these sample preparation strategies and MS analytical techniques allows for a multi-faceted approach to obtaining deep knowledge of crustacean peptidergic signaling pathways.

Integrating ultrasonic neuromodulation with fiber photometry

Ultrasound has been used to modulate neural activity in rodents and primates; however, combining ultrasound stimulation with in vivo imaging in freely moving animals has been challenging. Here, we design and validate a transducer to overcome these challenges in the rodent. We develop a head-mounted ultrasound transducer that can be combined with a fiber photometry system. This combination allows us to monitor ultrasound-evoked responses in striatal neurons in awake and freely moving animals. Together, this system allows for a high-resolution analysis of ultrasound-evoked biology at the level of both neural circuits and behavior in freely moving animals, critical to providing a mechanistic understanding of ultrasound neuromodulation.

Mapping brain circuits for murine maternal behavior triggered by pup calls

How sensory cues are integrated at the level of neural circuits to drive maternal behaviors remains incompletely understood. In a recent study, Valtcheva, Issa, and colleagues identified a previously unknown role for the posterior intralaminar (PIL) nucleus of the thalamus within the neural networks that mediate maternal behavior in mice induced by pup calls.

Knowledge mapping of the relationship between norepinephrine and memory: a bibliometric analysis.

Memory is a fundamental cognitive function for successful interactions with a complex environment. Norepinephrine (NE) is an essential component of catecholamine induced by emotional arousal, and numerous studies have demonstrated that NE is a key regulator in memory enhancement. We therefore conducted a bibliometric analysis to represent the knowledge pattern of the literature on the theme of NE-memory relationship. The WOSCC database was selected to extract literature published during 2003-2022. The collected data of annual production, global cooperation, research structure and hotspots were analyzed and visualized. Our results showed that research on the links between NE and memory displayed a considerable development trend over the last two decades. The USA had a leading position in terms of scientific outputs and collaborations. Meanwhile, University of California Irvine contributed the most publications. Benno Roozendaal and James McGaugh were the most prolific authors in this field, and Neurobiology of Learning and Memory had the highest number of publications on this topic. The research emphasis has evolved from memory-related diseases and brain regions to neural mechanisms for different types of memory at neural circuit levels. Our bibliometric analysis systematically analyzed the literature on the links between NE and memory from a bibliometric perspective. The demonstrated results of the knowledge mapping would provide valuable insights into the global research landscape.

The locus coeruleus-dorsal hippocampal CA1 pathway is involved in depression-induced perioperative neurocognitive disorders in adult mice.

Patients undergoing surgical anesthesia increasingly suffer from preoperative depression. Clinical studies have shown that depression is a risk factor for perioperative neurocognitive disorders (PNDs) in elder patients. However, the underlying mechanism, especially at the neural circuit level, remains poorly understood. Right carotid artery separation under sevoflurane and chronic social defeat stress (CSDS) in adult mice were used to establish surgical anesthesia and chronic depression models. Cognitive function was assessed by the Y maze and novel object recognition tests. A chemogenetic approach was used to modulate the locus coeruleus-dorsal hippocampal CA1 (LC-dCA1) circuit. Hippocampal synaptic alterations were evaluated by Golgi staining and whole-cell patch clamp recording. We found that CSDS induced synaptic impairments in dorsal hippocampal CA1 pyramidal neurons and cognitive deficits in adult mice after surgery under sevoflurane. Chemogenetic activation of the LC-dCA1 pathway significantly alleviated the CSDS-induced synaptic impairments and cognitive dysfunction. On the contrary, inhibition of this pathway could mimic CSDS-induced deficits. Furthermore, we showed that dopamine played an important role in CSDS-induced PNDs in adult mice after surgery/sevoflurane. Overall, our results have demonstrated a vital role for the LC-dCA1 pathway in CSDS-induced PNDs in adult mice undergoing surgery with sevoflurane anesthesia.

Research progress and thinking of acupuncture in anti-inflammation by regulating autonomic nerve system

The nervous system is the necessary condition for inducing the curative effect of acupuncture. Both the sympathetic and vagal nerve systems are widely distributed throughout the body and organically connect various systems and organs of the human body. In maintaining the coordination and unity of human physiological activities, it is in line with the holistic view and bidirectional regulation of acupuncture, and fits in with the meridian theory of "internally belonging to the Zang-fu organs and externally connecting with the limbs and joints". Acupuncture, one of the body surface stimulation therapies, can inhibit the inflammatory response via activating sympathetic/vagus nerve mediated anti-inflammatory pathways. The peripheral nerve innervating diffe-rent acupoints determines the different anti-inflammatory pathways of the autonomic nerve, and different acupuncture methods (stimulation form and stimulation amount) are important factors affecting the anti-inflammatory mechanism of the autonomic nerve. In the future, we should analyze the central integration mechanism between sympathetic nerve and vagus nerve regulated by acupuncture at the level of brain neural circuits, and clarify the "multi-target" advantage of acupuncture, so as to provide inspiration and reference for the study of neuroimmunological effects of acupuncture.

Brain energetics and the connectionist concept in cognitive neuroscience.

One of the central paradigms of modern neuroscience is the connectionist concept suggesting that the brain's cognitive functions are carried out at the level of neural networks through complex interactions among neurons. This concept considers neurons as simple network elements whose function is limited to generating electrical potentials and transmitting signals to other neurons. Here, I focus on the neuroenergetic aspect of cognitive functions and argue that many findings from this field challenge the concept that cognitive functions are performed exclusively at the level of neural circuits. Two of these findings are particularly foretelling. First, activation of the cerebral cortex in humans (sensory stimulation or solving cognitive problems) is not associated with a significant increase in energy demand. Second, the energetic cost of the brain per unit mass in primates, including Homo sapiens, is approximately proportional to the number of cerebral neurons but not to the number of synapses, the complexity of neural networks, or the level of brain's intellectual abilities. These findings contradict the predictions of the connectionist concept. Rather, they suggest that cognitive functions are generated by intraneuronal mechanisms that do not require much energy. In this context, interactions among neurons would serve to coordinate activities of neurons performing elementary cognitive functions. This function of the network mechanisms also does not require much energy.

Regulation of social interaction in mice by a frontostriatal circuit modulated by established hierarchical relationships

Social hierarchies exert a powerful influence on behavior, but the neurobiological mechanisms that detect and regulate hierarchical interactions are not well understood, especially at the level of neural circuits. Here, we use fiber photometry and chemogenetic tools to record and manipulate the activity of nucleus accumbens-projecting cells in the ventromedial prefrontal cortex (vmPFC-NAcSh) during tube test social competitions. We show that vmPFC-NAcSh projections signal learned hierarchical relationships, and are selectively recruited by subordinate mice when they initiate effortful social dominance behavior during encounters with a dominant competitor from an established hierarchy. After repeated bouts of social defeat stress, this circuit is preferentially activated during social interactions initiated by stress resilient individuals, and plays a necessary role in supporting social approach behavior in subordinated mice. These results define a necessary role for vmPFC-NAcSh cells in the adaptive regulation of social interaction behavior based on prior hierarchical interactions.

Neural mechanisms of social empathy in the anterior cingulate cortex

Empathy is a prosocial behavior that perceives the emotional state of others, expresses similar perceptions that match those of others, and mediates different social behaviors. Empathic behaviors for pain and fear also exist in primates and rodents. In the past decades, the neural mechanisms of empathy have been defined as a result of various sensations and perceptions, such as visual and hearing stimuli, which cause mirror activations in brain regions, such as the insular, the inferior frontal, and the medial frontal cortices, among which the anterior cingulate cortex (ACC) has been identified as a core region of the neural network that is associated with the empathic activity in mammals. Most studies on the neural mechanisms underlying empathy have been based on rodent models, which allowed for single-cell resolution mapping of neuronal activity; moreover, the application of optogenetic techniques in rodent models has led to a deeper delineation of neural circuits. Here, we review the role of the ACC in two behavioral paradigms, pain and fear empathy, in rodents at the neuronal and neural circuit levels. Understanding how the ACC mediates empathic behavior in the brain will provide new targets in the treatment for neuropsychiatric disorders characterized by empathic disorders.

Effects of Nonthermal Radiofrequency Stimulation on Neuronal Activity and Neural Circuit in Mice.

Whether the nonthermal effects of radiofrequency radiation (RFR) exist and how nonthermal RFR acts on the nervous system are unknown. An animal model of spatial memory impairment is established by exposing mice to 2856-MHz RFR in the range of thermal noise (≤1 °C). Glutamate release in the dorsal hippocampus (dHPC) CA1 region is not significantly changed after radiofrequency exposure, whereas dopamine release is reduced. Importantly, RFR enhances glutamatergic CA1 pyramidal neuron calcium activity by nonthermal mechanisms, which recover to the basal level with RFR termination. Furthermore, suppressed dHPC dopamine release induced by radiofrequency exposure is due to decreased density of dopaminergic projections from the locus coeruleus to dHPC, and artificial activation of dopamine axon terminals or D1 receptors in dHPC CA1 improve memory damage in mice exposed to RFR. These findings indicate that nonthermal radiofrequency stimulation modulates ongoing neuronal activity and affects nervous system function at the neural circuit level.

Convergent Energy State-Dependent Antagonistic Signaling by Cocaine- and Amphetamine-Regulated Transcript (CART) and Neuropeptide Y (NPY) Modulates the Plasticity of Forebrain Neurons to Regulate Feeding in Zebrafish.

Dynamic reconfiguration of circuit function subserves the flexibility of innate behaviors tuned to physiological states. Internal energy stores adaptively regulate feeding-associated behaviors and integrate opposing hunger and satiety signals at the level of neural circuits. Across vertebrate lineages, the neuropeptides cocaine- and amphetamine-regulated transcript (CART) and neuropeptide Y (NPY) have potent anorexic and orexic functions, respectively, and show energy-state-dependent expression in interoceptive neurons. However, how the antagonistic activities of these peptides modulate circuit plasticity remains unclear. Using behavioral, neuroanatomical, and activity analysis in adult zebrafish of both sexes, along with pharmacological interventions, we show that CART and NPY activities converge on a population of neurons in the dorsomedial telencephalon (Dm). Although CART facilitates glutamatergic neurotransmission at the Dm, NPY dampens the response to glutamate. In energy-rich states, CART enhances NMDA receptor (NMDAR) function by protein kinase A/protein kinase C (PKA/PKC)-mediated phosphorylation of the NR1 subunit of the NMDAR complex. Conversely, starvation triggers NPY-mediated reduction in phosphorylated NR1 via calcineurin activation and inhibition of cAMP production leading to reduced responsiveness to glutamate. Our data identify convergent integration of CART and NPY inputs by the Dm neurons to generate nutritional state-dependent circuit plasticity that is correlated with the behavioral switch induced by the opposing actions of satiety and hunger signals.SIGNIFICANCE STATEMENT Internal energy needs reconfigure neuronal circuits to adaptively regulate feeding behavior. Energy-state-dependent neuropeptide release can signal energy status to feeding-associated circuits and modulate circuit function. CART and NPY are major anorexic and orexic factors, respectively, but the intracellular signaling pathways used by these peptides to alter circuit function remain uncharacterized. We show that CART and NPY-expressing neurons from energy-state interoceptive areas project to a novel telencephalic region, Dm, in adult zebrafish. CART increases the excitability of Dm neurons, whereas NPY opposes CART activity. Antagonistic signaling by CART and NPY converge onto NMDA-receptor function to modulate glutamatergic neurotransmission. Thus, opposing activities of anorexic CART and orexic NPY reconfigure circuit function to generate flexibility in feeding behavior.

Pushing the Frontiers: Optogenetics for Illuminating the Neural Pathophysiology of Bipolar Disorder.

Bipolar disorder (BD), a disabling mental disorder, is featured by the oscillation between episodes of depression and mania, along with disturbance in the biological rhythms. It is on an urgent demand to identify the intricate mechanisms of BD pathophysiology. Based on the continuous progression of neural science techniques, the dysfunction of circuits in the central nervous system was currently thought to be tightly associated with BD development. Yet, challenge exists since it depends on techniques that can manipulate spatiotemporal dynamics of neuron activity. Notably, the emergence of optogenetics has empowered researchers with precise timing and local manipulation, providing a possible approach for deciphering the pathological underpinnings of mental disorders. Although the application of optogenetics in BD research remains preliminary due to the scarcity of valid animal models, this technique will advance the psychiatric research at neural circuit level. In this review, we summarized the crucial aberrant brain activity and function pertaining to emotion and rhythm abnormities, thereby elucidating the underlying neural substrates of BD, and highlighted the importance of optogenetics in the pursuit of BD research.