Interconnected Neural Circuits Research Articles

The Relative Contribution of Glycine-GABA Cotransmission in the Core of the Respiratory Network.

The preBötzinger complex (preBötC) and the Bötzinger complex (BötC) are interconnected neural circuits that are involved in the regulation of breathing in mammals. Fast inhibitory neurotransmission is known to play an important role in the interaction of these two regions. Moreover, the corelease of glycine and GABA has been described in the respiratory network, but the contribution of the individual neurotransmitter in different pathways remains elusive. In sagittal brainstem slices of neonatal mice, we employed a laser point illumination system to activate glycinergic neurons expressing channelrhodopsin-2 (ChR2). This approach allowed us to discern the contribution of glycine and GABA to postsynaptic currents of individual whole-cell clamped neurons in the preBötC and BötC through the application of glycine and GABA receptor-specific antagonists. In more than 90% of the recordings, both transmitters contributed to the evoked IPSCs, with the glycinergic component being larger than the GABAergic component. The GABAergic component appeared to be most prominent when stimulation and recording were both performed within the preBötC. Taken together, our data suggest that GABA-glycine cotransmission is the default mode in the respiratory network of neonatal mice with regional differences that may be important in tuning the network activity.

Executive functions, self-regulation and social media for peace-based inclusive education

This article comprehensively explores the critical interplay between executive functions (EFs), self-regulation, and social media in promoting a peaceful and inclusive educational environment. The study emphasizes the significance of EFs in regulating cognitive processes and coping with new challenges, focusing on the prefrontal cortex (PFC) and its interconnected neural circuits. Addressing the relevance of EFs in conflict resolution, emotional regulation, and metacognitive practices, the research investigates how they contribute to constructive conflict-resolution, emotional maturity, and responsible online behavior in educational settings. Furthermore, the bidirectional relationship between prosocial behaviors and EFs is explored, revealing their mutual reinforcement during early childhood and beyond. The article discusses the benefits and challenges of social media in educational contexts, highlighting the importance of mindful usage to promote positive interactions and empathy among students, educators, and stakeholders. Adopting a holistic approach, the study examines successful self-regulation practices and approaches that empower individuals to navigate negative emotions and cultivate positive relationships within groups. Additionally, the review sheds light on the potential implications of EFs and self-regulation in neurodevelopmental disorders, such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). It identifies shared genetic bases and neurobiological underpinnings, offering valuable insights for developing targeted interventions to enhance executive function skills in affected populations. The findings have practical implications for professionals in education, parents, and policymakers, emphasizing the importance of nurturing emotional regulation, promoting metacognitive practices, and ensuring responsible social media use to create a harmonious and inclusive educational environment. The article aims to provide valuable insights for researchers and practitioners seeking to cultivate empathy, support positive conflict resolution, and facilitate the holistic development of students and stakeholders in educational and intimate learning environments.

Bayesian network mediation analysis with application to the brain functional connectome.

The brain functional connectome, the collection of interconnected neural circuits along functional networks, facilitates a cutting-edge understanding of brain functioning, and has a potential to play a mediating role within the effect pathway between an exposure and an outcome. While existing mediation analytic approaches are capable of providing insight into complex processes, they mainly focus on a univariate mediator or mediator vector, without considering network-variate mediators. To fill the methodological gap and accomplish this exciting and urgent application, in the article, we propose an integrative mediation analysis under a Bayesian paradigm with networks entailing the mediation effect. To parameterize the network measurements, we introduce individually specified stochastic block models with unknown block allocation, and naturally bridge effect elements through the latent network mediators induced by the connectivity weights across network modules. To enable the identification of truly active mediating components, we simultaneously impose a feature selection across network mediators. We show the superiority of our model in estimating different effect components and selecting active mediating network structures. As a practical illustration of this approach's application to network neuroscience, we characterize the relationship between a therapeutic intervention and opioid abstinence as mediated by brain functional sub-networks.

From a Pathophysiological Concept to a New Drug

Although antipsychotics were discovered over fifty years ago, it took another decade until dopamine antagonism was demonstrated as central to their clinical effectiveness. Since accumulated evidence implicates the dopamine system in the pathophysiology of schizophrenia, all licensed first-line treatments operate primarily via antagonism of the dopamine D2 receptor. However, dopamine D2 receptor blockade does not effectively treat negative, cognitive and affective symptoms and, in a significant proportion of patients, it does not improve positive symptoms either. Therefore, additional neurochemical targets were considered. The “revised dopamine hypothesis” proposes that positive symptoms emerge due to hyperactive dopamine transmission in mesolimbic areas, while hypoactive dopamine transmission via the mesocortical pathway in the prefrontal cortex is linked to negative, cognitive, and partly affective symptoms. In this context, the role of D3 receptors were recognised. However, there is also evidence for the involvement of other neurotransmitter systems, suggesting that dopamine signalling relies on a suite of receptors that are thought to either facilitate or inhibit neurotransmitter activity through several interconnected neural circuits. Furthermore, there seem to be clusters of symptoms that cross the boundaries of disorders. Symptoms having similar pathophysiology at neurotransmitter level can be treated with the same drug or class of drugs. Thus, one particular drug might be effective in more than one indication. This lecture aims to illustrate the process of a new drug development by explaining how the underlying pathophysiology on receptor level impacts clinical studies and vice versa.DisclosureEmployee of Gedeon Richter Plc.

Behavioural analysis of single-cell aneural ciliate, Stentor roeseli, using machine learning approaches.

There is still a significant gap between our understanding of neural circuits and the behaviours they compute-i.e. the computations performed by these neural networks (Carandini 2012 Nat. Neurosci.15, 507-509. (doi:10.1038/nn.3043)). Cellular decision-making processes, learning, behaviour and memory formation-all that have been only associated with animals with neural systems-have also been observed in many unicellular aneural organisms, namely Physarum, Paramecium and Stentor (Tang & Marshall2018 Curr. Biol.28, R1180-R1184. (doi:10.1016/j.cub.2018.09.015)). As these are fully functioning organisms, yet being unicellular, there is a much better chance to elucidate the detailed mechanisms underlying these learning processes in these organisms without the complications of highly interconnected neural circuits. An intriguing learning behaviour observed in Stentor roeseli (Jennings 1902 Am. J. Physiol. Legacy Content8, 23-60. (doi:10.1152/ajplegacy.1902.8.1.23)) when stimulated with carmine has left scientists puzzled for more than a century. So far, none of the existing learning paradigm can fully encapsulate this particular series of five characteristic avoidance reactions. Although we were able to observe all responses described in the literature and in a previous study (Dexter et al. 2019), they do not conform to any particular learning model. We then investigated whether models inferred from machine learning approaches, including decision tree, random forest and feed-forward artificial neural networks could infer and predict the behaviour of S. roeseli. Our results showed that an artificial neural network with multiple 'computational' neurons is inefficient at modelling the single-celled ciliate's avoidance reactions. This has highlighted the complexity of behaviours in aneural organisms. Additionally, this report will also discuss the significance of elucidating molecular details underlying learning and decision-making processes in these unicellular organisms, which could offer valuable insights that are applicable to higher animals.

Peripheral nerve injury attenuates stress-induced Fos-family expression in the Locus Coeruleus of male Sprague-Dawley rats

The ability to cope with acute stressors is impaired in people with chronic neuropathic injuries. The regulation of stress coping responses depends critically on several parallel interconnected neural circuits, one of which originates in the Locus Coeruleus. In rats, chronic constriction injury (CCI) and acute stress each modulate noradrenergic activity of the Locus Coeruleus (LC) although with different temporal patterns. This study investigated the effects of CCI on the neuronal activity of the LC to acute restraint stress using the immunohistochemical detection of Fos-family protein expression. Male Sprague-Dawley rats underwent CCI surgery and 11 days later were restrained for 15 min. The number and location of single-labelled neurons (c-Fos, FosB/ΔFosB and tyrosine hydroxylase (TH) immunoreactive) neurons and double labelled neurons (c-Fos, or FosB/ΔFosB with TH) were quantified for the LC and surrounding regions. Comparisons were made with rats that underwent sham surgery or anaesthesia (20 min). Restraint triggered a struggling response in all rats. CCI attenuated restraint-induced Fos expression in LC neurons. A significant proportion (30–50%) of these LC Fos positive neurons did not contain TH. These data suggest that nerve injury might impair the ordinary cellular response of the LC to an acute stress. The association of stress-related disorders in people with neuropathic injuries suggests that the observations made in this study may reflect a part of the mechanism underlying these clinical comorbidities.

1. Dissecting the Neural Circuits for Motivated Behavior

In order to survive and effectively navigate an ever-changing and unpredictable environment, organisms must readily adapt their behavior to seek out needed resources, while simultaneously avoiding life-threatening situations. These opposing processes are controlled by neural circuitry that is readily engaged by both environmental and physiological factors to promote behavioral output. The work of my lab studies the precise neural circuits that control both reward and aversive-related behavioral responses. By utilizing optogenetic and other circuit mapping tools, we aim to delineate the precise functional synaptic connections between molecularly distinct neuronal populations that are critical for the generation of these critical behavioral states. A holistic understanding of the interconnected neural circuit elements that mediate diverse motivational behaviors will likely provide important insight into a variety of complex neurological and neuropsychiatric illnesses such as addiction, anxiety, and depression.

A Cold-Blooded View on Adult Neurogenesis.

During brain development, highly complex and interconnected neural circuits are established. This intricate wiring needs to be robust to faithfully perform adult brain function throughout life, but at the same time offer room for plasticity to integrate new information. In the mammalian brain, adult-born neurons are produced in restricted niches harboring neural stem cells. In the fruit fly Drosophila, low-level adult neurogenesis arising from a dispersed population of neural progenitors has recently been detected in the optic lobes. Strikingly, these normally quiescent neural stem cells proliferate upon brain injury and produce new neurons for brain regeneration. Here, we review adult neurogenesis in crustaceans and insects and highlight that neurogenesis in the visual system is prominent in arthropods, but its role and underlying mechanisms are unclear. Moreover, we discuss how the study of damage-responsive progenitor cells in Drosophila may help to understand robust regenerative neurogenesis and open new avenues to enhance brain repair after injury or stroke in humans.

All for One But Not One for All: Excitatory Synaptic Scaling and Intrinsic Excitability Are Coregulated by CaMKIV, Whereas Inhibitory Synaptic Scaling Is Under Independent Control.

Neocortical circuits use a family of homeostatic plasticity mechanisms to stabilize firing, including excitatory and inhibitory synaptic scaling and homeostatic intrinsic plasticity (Turrigiano and Nelson, 2004). All three mechanisms can be induced in tandem in cultured rat neocortical pyramidal neurons by chronic manipulations of firing, but it is unknown whether they are coinduced by the same activity-sensors and signaling pathways, or whether they are under independent control. Calcium/calmodulin-dependent protein kinase type IV (CaMKIV) is a key sensory/effector in excitatory synaptic scaling that senses perturbations in firing through changes in calcium influx, and translates this into compensatory changes in excitatory quantal amplitude (Ibata et al., 2008; Goold and Nicoll, 2010). Whether CaMKIV also controls inhibitory synaptic scaling and intrinsic homeostatic plasticity was unknown. To test this we manipulated CaMKIV signaling in individual neurons using dominant-negative (dn) or constitutively-active (ca) forms of nuclear-localized CaMKIV and measured the induction of all three forms of homeostatic plasticity. We found that excitatory synaptic scaling and intrinsic plasticity were bidirectionally coinduced by these manipulations. In contrast, these cell-autonomous manipulations had no impact on inhibitory quantal amplitude. Finally, we found that spontaneous firing rates were shifted up or down by dnCaMKIV or caCaMKIV, respectively, suggesting that uncoupling CaMKIV activation from activity generates an error signal in the negative feedback mechanism that controls firing rates. Together, our data show that excitatory synaptic scaling and intrinsic excitability are tightly coordinated through bidirectional changes in the same signaling pathway, whereas inhibitory synaptic scaling is sensed and regulated through an independent control mechanism.SIGNIFICANCE STATEMENT Maintaining stable function in highly interconnected neural circuits is essential for preventing circuit disorders, and is accomplished through a set of negative feedback mechanisms that sense and compensate for perturbations in activity. These "homeostatic" mechanisms can target synaptic excitation, synaptic inhibition, and intrinsic excitability, but whether they are independently controlled is not known. We find that synaptic excitation and intrinsic excitability are coregulated in individual neurons through CaMKIV signaling, which is tightly controlled by neuronal activity. In contrast, synaptic inhibition is unaffected by changes in firing or CaMKIV signaling in individual neurons. These results show that circuit stability is controlled both through cell-autonomous mechanisms that regulate some aspects of excitability, as well as circuit-level mechanisms that adjust inhibition.

Cerebellum in Neurological Disorders: A Review on the Role of Inter-Connected Neural Circuits

Cerebellum in Neurological Disorders: A Review on the Role of Inter-Connected Neural Circuits

Prefrontal cortex and mediodorsal thalamus reduced connectivity is associated with spatial working memory impairment in rats with inflammatory pain

The medial prefrontal cortex (mPFC) and the mediodorsal thalamus (MD) form interconnected neural circuits that are important for spatial cognition and memory, but it is not known whether the functional connectivity between these areas is affected by the onset of an animal model of inflammatory pain. To address this issue, we implanted 2 multichannel arrays of electrodes in the mPFC and MD of adult rats and recorded local field potential activity during a food-reinforced spatial working memory task. Recordings were performed for 3weeks, before and after the establishment of the pain model. Our results show that inflammatory pain caused an impairment of spatial working memory performance that is associated with changes in the activity of the mPFC–MD circuit; an analysis of partial directed coherence between the areas revealed a global decrease in the connectivity of the circuit. This decrease was observed over a wide frequency range in both the frontothalamic and thalamofrontal directions of the circuit, but was more evident from MD to mPFC. In addition, spectral analysis revealed significant oscillations of power across frequency bands, namely with a strong theta component that oscillated after the onset of the painful condition. Finally, our data revealed that chronic pain induces an increase in theta/gamma phase coherence and a higher level of mPFC–MD coherence, which is partially conserved across frequency bands. The present results demonstrate that functional disturbances in mPFC–MD connectivity are a relevant cause of deficits in pain-related working memory.

Impaired spatial memory performance in a rat model of neuropathic pain is associated with reduced hippocampus-prefrontal cortex connectivity.

Chronic pain patients commonly complain of working memory deficits, but the mechanisms and brain areas underlying this cognitive impairment remain elusive. The neuronal populations of the mPFC and dorsal CA1 (dCA1) are well known to form an interconnected neural circuit that is crucial for correct performance in spatial memory-dependent tasks. In this study, we investigated whether the functional connectivity between these two areas is affected by the onset of an animal model of peripheral neuropathic pain. To address this issue, we implanted two multichannel arrays of electrodes in the mPFC and dCA1 of rats and recorded the neuronal activity during a food-reinforced spatial working memory task in a reward-based alternate trajectory maze. Recordings were performed for 3 weeks, before and after the establishment of the spared nerve injury model of neuropathy. Our results show that the nerve lesion caused an impairment of working memory performance that is temporally associated with changes in the mPFC populational firing activity patterns when the animals navigated between decision points-when memory retention was most needed. Moreover, the activity of both recorded neuronal populations after the nerve injury increased their phase locking with respect to hippocampal theta rhythm. Finally, our data revealed that chronic pain reduces the overall amount of information flowing in the fronto-hippocampal circuit and induces the emergence of different oscillation patterns that are well correlated with the correct/incorrect performance of the animal on a trial-by-trial basis. The present results demonstrate that functional disturbances in the fronto-hippocampal connectivity are a relevant cause for pain-related working memory deficits.

Merger Fever: Can Two Separate Mechanisms Work Together to Explain Why We Drink?

Merger Fever: Can Two Separate Mechanisms Work Together to Explain Why We Drink?

Triple-pulse TMS to study interactions between neural circuits in human cortex

Transcranial magnetic stimulation (TMS) is a widely used brain stimulation technique that allows noninvasive examination of different excitatory and inhibitory circuits at the systems level in the intact human brain. In recent years, considerable knowledge has been accumulated about the physiology ofseveral of these facilitatory and inhibitory processes individually. However, activity in the corresponding neural circuits is not independent of each other. This paper reviews the experiments using triple-pulse TMS that are specifically designed to study interactions between intracortical circuits. These studies have provided evidence for a complex network of interconnected neural circuits within and across cerebral hemispheres. The current knowledge about the functional organization of this network, its pharmacology and functional implications for human motor control are discussed in detail. These findings have clinical relevance because specific interactions between neural circuits may be impaired in neurologic and psychiatric disorders. We conclude that triple-pulse TMS studies will help to integrate and better understand the physiologic processes involved in human motor behavior.

007 Mild cognitive impairment

: Mild cognitive impairment (MCI) is a syndromic label for people with informant-corroborated memory problems and evidence of memory impairment on formal testing in the absence of more pervasive deficits...

Fiber connections of the compact division of the posterior pallial amygdala and lateral part of the bed nucleus of the stria terminalis in the pigeon (Columba livia)

The compact division of the posterior pallial amygdala (PoAc) and lateral part of the bed nucleus of the stria terminalis (BSTL) are components of the limbic system in the pigeon brain. In this study, we examined the position and fiber connections of these two nuclei by using Nissl staining and tract-tracing methods. PoAc occupies a central division in the posterior pallial amygdala. BSTL faces the ventral horn of the lateral ventricle and extends between A 7.25 and A 10.50. PoAc and BSTL connect bidirectionally by the stria terminalis. PoAc connects reciprocally with two nuclear groups in the cerebrum: 1) a continuum consisting of the caudoventral nidopallium, lateral part of the caudoventral nidopallium (NCVl), subnidopallium beneath NCVl, and piriform cortex and 2) rostral areas of the hemisphere, including the frontolateral and frontomedial nidopallium and the densocellular part of the hyperpallium. Extratelencephalic projections of PoAc terminate in the dorsomedial thalamic nuclei and reach the lateral hypothalamic area via the hypothalamic part of the occipito-mesencephalic tract. BSTL also connects reciprocally with two main regions: 1) the same continuum as for PoAc projections, except the piriform cortex and 2) rostral areas of the hemisphere, including the olfactory tubercle and nucleus accumbens. Extratelencephalic reciprocal connections are with the substantia nigra, nucleus subceruleus dorsalis, parabrachial nucleus, locus coeruleus, and nucleus of the solitary tract. The dorsomedial subdivision of the hippocampal formation projects massively to PoAc and BSTL. These findings indicate that PoAc and BSTL are important components of an interconnected neural circuit involving widespread regions of the neuraxis and mediating limbic-visceral functions.

Amygdala-Prefrontal Cortical Circuitry Regulates Effort-Based Decision Making

The basolateral amygdala (BLA) and the anterior cingulate cortex (ACC) region of the prefrontal cortex form an interconnected neural circuit that may mediate certain types of decision-making processes. The present study assessed the role of this pathway in effort-based decision making using a cost-benefit T-maze task. Rats were given a choice of obtaining a high reward by climbing a 30-cm barrier in 1 arm (4 pellets; high-reward [HR] arm) or a small reward in the other arm with no barrier (2 pellets; low-reward [LR] arm). In Experiment 1, bilateral inactivation of the BLA via infusion of bupivacaine impaired decision making, reducing the preference for the HR arm. This effect was not due to spatial or motor deficits because BLA inactivation did not alter behavior when the amount of effort required to obtain either reward was equalized by placing a 2nd barrier in the LR arm. In Experiment 2, disconnection between the BLA and ACC, entailing a unilateral BLA inactivation combined with a contralateral ACC inactivation also impaired decision making. These data suggest that the serial transfer of information between the BLA and ACC guides response selection when evaluating the value of an expected outcome relative to the costs of performing a particular action.

Effects of melatonin on oxidative stress and spatial memory impairment induced by acute ethanol treatment in rats.

Melatonin has recently been suggested as an antioxidant that may protect neurons from oxidative stress. Acute ethanol administration produces both lipid peroxidation as an indicator of oxidative stress in the brain and impairs water-maze performance in spatial learning and memory tasks. The present study investigated the effect of melatonin against ethanol-induced oxidative stress and spatial memory impairment. The Morris water maze was used to evaluate the cognitive functions of rats. Thiobarbituric acid reactive substances (TBARS), which are the indicators of lipid peroxidation, and the activities of antioxidative enzymes (glutathione peroxidase and superoxide dismutase) were measured in the rat hippocampus and prefrontal cortex which form interconnected neural circuits for spatial memory. Acute administration of ethanol significantly increased TBARS levels in the hippocampus. Combined melatonin-ethanol treatment caused a significant increase in glutathione peroxidase activities and a significant decrease of TBARS in the rat hippocampus. In the prefrontal cortex, there was only a significant decrease of TBARS levels in the combined melatonin-ethanol receiving group as compared to the ethanol-treated group. Melatonin did not affect the impairment of spatial memory due to acute ethanol exposure, but melatonin alone had a positive effect on water maze performances. Our study demonstrated that melatonin decreased ethanol-induced lipid peroxidation and increased glutathione peroxidase activity in the rat hippocampus.

Gating of Hippocampal-Evoked Activity in Prefrontal Cortical Neurons by Inputs from the Mediodorsal Thalamus and Ventral Tegmental Area

Projections from the hippocampus, the mediodorsal thalamus (MD), and the ventral tegmental area (VTA) form interconnected neural circuits that converge in the prefrontal cortex (PFC) to participate in the regulation of executive functions. The present study assessed the roles that the MD and VTA play in regulating the hippocampal-PFC pathway using extracellular single-unit recordings in urethane-anesthetized rats. MD stimulation inhibited PFC neuron firing (approximately 100 msec duration) evoked by fimbria/fornix (FF) stimulation in a majority of neurons tested. However, this effect was reduced if activation of thalamocortical inputs occurred almost simultaneously (10 msec) with stimulation of the FF. In a separate population of neurons, burst stimulation of the MD produced a short-term (approximately 100 msec) inhibition or facilitation of FF-evoked firing in 66 and 33% of PFC neurons, respectively. Moreover, tetanic stimulation of the MD caused a longer-lasting (approximately 5 min) potentiation of FF-evoked firing. Burst stimulation of the VTA inhibited FF-evoked firing in a frequency-dependent manner: firing evoked by higher-frequency trains of pulses to the FF was less inhibited than firing evoked by single-pulse stimulation. The inhibitory actions of VTA stimulation were augmented by D1 receptor antagonism and attenuated by D2 and D4 antagonists. Moreover, stimulation of the MD 10 msec before stimulation of the FF attenuated the VTA-mediated inhibition of evoked firing. Thus, both the MD and VTA exert a complex gating action over PFC neural activity, either facilitating or inhibiting firing in the hippocampal-PFC pathway depending on the frequency and relative timing of the arrival of afferent input.

Thalamic–Cortical–Striatal Circuitry Subserves Working Memory during Delayed Responding on a Radial Arm Maze

The medial dorsal nuclei of the thalamus (MDNt), the prefrontal cortex, and the ventral striatum form an interconnected neural circuit that may subserve certain types of working memory. The present series of experiments investigated functional interactions between these brain regions in rats during the performance of delayed and nondelayed spatially cued radial-arm maze tasks. In Experiment 1, transient inactivation of the MDNt by a bilateral injection of lidocaine selectively disrupted performance on a delayed task but not on a nondelayed random foraging version of the radial arm maze task. In Experiment 2, asymmetrical lidocaine injections into the MDNt on one side of the brain and the prefrontal cortex on the other transiently disconnected these two brain regions and significantly impaired foraging during the delayed task. Similarly, disconnections between the prefrontal cortex and the nucleus accumbens also disrupted foraging on this task, whereas disconnections between the MDNt and the nucleus accumbens had no effect. These data suggest that serial transmission of information among the MDNt, the prefrontal cortex, and the nucleus accumbens is required when trial-unique, short-term spatial memory is used to guide prospective search behavior. The results are discussed with respect to a distributed neural network linking limbic, thalamic, cortical, and striatal regions, which mediates executive functions of working memory.