Rostral and caudal BLA engage distinct circuits in the prelimbic and infralimbic PFC

Connections from the basolateral amygdala (BLA) to medial prefrontal cortex (PFC) regulate memory and emotion and become disrupted in neuropsychiatric disorders. We hypothesized that the diverse roles attributed to interactions between the BLA and PFC reflect multiple circuits nested within a wider network. To assess these circuits, we first used anatomy to show that the rostral BLA (rBLA) and caudal BLA (cBLA) differentially project to prelimbic (PL) and infralimbic (IL) subregions of the PFC, respectively. We then combined in vivo silicon probe recordings and optogenetics to show that rBLA primarily engages PL, whereas cBLA mainly influences IL. Using ex vivo whole-cell recordings and optogenetics, we then assessed which neuronal subtypes are targeted, showing that rBLA preferentially drives layer 2 (L2) cortico-amygdalar (CA) neurons in PL, whereas cBLA drives layer 5 (L5) pyramidal tract (PT) cells in IL. Lastly, we used soma-tagged optogenetics to explore the local circuits linking superficial and deep layers of PL, showing how rBLA can also impact L5 PT cells. Together, our findings delineate how subregions of the BLA target distinct networks within the PFC to have different influence on prefrontal output.

Higher-order interaction of brain microstructural and functional connectome

Despite a relatively fixed anatomical structure, the human brain can support rich cognitive functions, triggering particular interest in investigating structure-function relationships. Myelin is a vital brain microstructure marker, yet the individual microstructure-function relationship is poorly understood. Here, we explore the brain microstructure-function relationships using a higher-order framework. Global (network-level) higher-order microstructure-function relationships negatively correlate with male participants' personality scores and decline with aging. Nodal (node-level) higher-order microstructure-function relationships are not aligned uniformly throughout the brain, being stronger in association cortices and lower in sensory cortices, showing gender differences. Notably, higher-order microstructure-function relationships are maintained from the whole-brain to local circuits, which uncovers a compelling and straightforward principle of brain structure-function interactions. Additionally, targeted artificial attacks can disrupt these higher-order relationships, and the main results are robust against several factors. Together, our results increase the collective knowledge of higher-order structure- function interactions that may underlie cognition, individual differences, and aging.

A specialized spinal circuit for command amplification and directionality during escape behavior

In vertebrates, action selection often involves higher cognition entailing an evaluative process. However, urgent tasks, such as defensive escape, require an immediate implementation of the directionality of escape trajectory, necessitating local circuits. Here we reveal a specialized spinal circuit for the execution of escape direction in adult zebrafish. A central component of this circuit is a unique class of segmentally repeating cholinergic V2a interneurons expressing the transcription factor Chx10. These interneurons amplify brainstem-initiated escape commands and rapidly deliver the excitation via a feedforward circuit to all fast motor neurons and commissural interneurons to direct the escape maneuver. The information transfer within this circuit relies on fast and reliable axo-axonic synaptic connections, bypassing soma and dendrites. Unilateral ablation of cholinergic V2a interneurons eliminated escape command propagation. Thus, in vertebrates, local spinal circuits can implement directionality of urgent motor actions vital for survival.

The Development of the Mesoprefrontal Dopaminergic System in Health and Disease

Midbrain dopaminergic neurons located in the substantia nigra and the ventral tegmental area are the main source of dopamine in the brain. They send out projections to a variety of forebrain structures, including dorsal striatum, nucleus accumbens, and prefrontal cortex (PFC), establishing the nigrostriatal, mesolimbic, and mesoprefrontal pathways, respectively. The dopaminergic input to the PFC is essential for the performance of higher cognitive functions such as working memory, attention, planning, and decision making. The gradual maturation of these cognitive skills during postnatal development correlates with the maturation of PFC local circuits, which undergo a lengthy functional remodeling process during the neonatal and adolescence stage. During this period, the mesoprefrontal dopaminergic innervation also matures: the fibers are rather sparse at prenatal stages and slowly increase in density during postnatal development to finally reach a stable pattern in early adulthood. Despite the prominent role of dopamine in the regulation of PFC function, relatively little is known about how the dopaminergic innervation is established in the PFC, whether and how it influences the maturation of local circuits and how exactly it facilitates cognitive functions in the PFC. In this review, we provide an overview of the development of the mesoprefrontal dopaminergic system in rodents and primates and discuss the role of altered dopaminergic signaling in neuropsychiatric and neurodevelopmental disorders.

Local neuronal excitation and global inhibition during epileptic fast ripples in humans

Understanding the neuronal basis of epileptiform activity is a major challenge in neurology. Interictal epileptiform discharges are associated with fast ripples (FRs, >200 Hz) in the local field potential (LFP) and are a promising marker of the epileptogenic zone. Here, by using a novel hybrid macro-micro depth electrode, combining classic depth recording of LFP and two or three tetrodes enabling up to 15 neurons in local circuits to be recorded simultaneously, we have characterized neuronal responses to FRs on the same hybrid and other electrodes targeting other brain regions. While FRs were associated with increased neuronal activity in local circuits only, they were followed by inhibition in large-scale networks. Neuronal responses to FRs were homogeneous in local networks but differed across brain areas. Similarly, post-FR inhibition varied across recording locations and subjects and was shorter than typical inter-FR intervals, suggesting that this inhibition is a fundamental refractory process for the networks. These findings demonstrate that FRs engage local and global networks and point to network features that pave the way for new diagnostic and therapeutic strategies.

Heterogeneous side-effects of cortical inactivation in behaving animals

Cortical inactivation represents a key causal manipulation that allows the study of cortical circuits and their impact on behavior. A key assumption in these studies is that the neurons in the target area become silent while the surrounding cortical tissue is only negligibly impacted. However, individual neurons are embedded in complex local circuits comprised of excitatory and inhibitory cells with connections extending hundreds of microns. This raises the possibility that silencing one part of the network could induce complex, unpredictable activity changes in neurons outside the targeted inactivation zone. These off-target side effects can potentially complicate interpretations of inactivation manipulations, especially when they are related to changes in behavior. Here, we demonstrate that optogenetic inactivation of glutamatergic neurons in the superficial layers of monkey V1 induces robust suppression at the light-targeted site, but destabilizes stimulus responses in the neighboring, untargeted network. We identified 4 types of stimulus-evoked neuronal responses within a cortical column, ranging from full suppression to facilitation, and a mixture of both. Mixed responses were most prominent in middle and deep cortical layers. Importantly, these results demonstrate that response modulation driven by lateral network connectivity is diversely implemented throughout a cortical column. Furthermore, consistent behavioral changes induced by optogenetic inactivation were only achieved when cumulative network activity was homogeneously suppressed. Therefore, careful consideration of the full range of network changes outside the inactivated cortical region is required, as heterogeneous side-effects can confound interpretation of inactivation experiments.

Nitric Oxide Regulates GluA2-Lacking AMPAR Contribution to Synaptic Transmission of CA1 Apical but Not Basal Dendrites

The mechanisms of synaptic plasticity differ in distinct local circuits. In the CA1 region of the hippocampus, the mechanisms of long-term potentiation (LTP) at apical dendrites in stratum radiatum and basal dendrites in stratum oriens involve different molecular cascades. For instance, participation of nitric oxide in LTP induction was shown to be necessary only for apical dendrites. This phenomenon may play a key role in information processing in CA1, and one of the reasons for this difference may be differing synaptic characteristics in these regions. Here, we compared the synaptic responses to stimulation of apical and basal dendrites of CA1 pyramidal neurons and found a difference in the current–voltage characteristics of these inputs, which is presumably due to a distinct contribution of GluA2-lacking AMPA receptors to synaptic transmission. In addition, we obtained data that indicate the presence of these receptors in pyramidal dendrites in both stratum radiatum and stratum oriens. We also demonstrated that inhibition of NO synthase reduced the contribution of GluA2-lacking AMPA receptors at apical but not basal dendrites, and inhibition of soluble guanylate cyclase did not affect this phenomenon.

Inhibitory Circuits in the Basolateral Amygdala in Aversive Learning and Memory

Neural circuits in the basolateral amygdala (BLA) play a pivotal role in the learning and memory formation, and processing of emotionally salient experiences, particularly aversive ones. A diverse population of GABAergic neurons present in the BLA orchestrate local circuits to mediate emotional memory functions. Targeted manipulation of GABAergic neuronal subtypes has shed light on cell-type specific functional roles in the fear learning and memory, revealing organizing principles for the operation of inhibitory circuit motifs in the BLA.

Optical Probing of Local Membrane Potential with Fluorescent Polystyrene Beads

Studying the electrical activity in single cells and in local circuits of excitable cells, like neurons, requires an easy to use and high throughput methodology that enables the measurement of membrane potential. Studying the electrical properties in particular sub-compartments of neurons, or in a specific type of neurons produces additional complexity. An optical voltage-imaging technique that allows high spatial and temporal resolution could be an ideal solution. However, most of the valid voltage imaging techniques are nonspecific; The ones that are more site-directed require much pre-work and specific adaptations in addition to other disadvantages. Here, a new technique for membrane voltage imaging, based on FRET between fluorescent polystyrene (FPS) beads and Dipicrylamine (DPA) is explored. Not only fluorescent intensity is demonstrated to be correlated with membrane potential, but more importantly, single particle voltage detection is demonstrated. Among other advantages, FPS beads can be synthesized with functional surface groups, and be further targeted to specific proteins via conjugation of recognition molecules. Therefore, FPS beads, in the presence of DPA, constitute single-particle detectors for membrane voltage, with a potential to be localized to specific membrane compartments. This new and accessible platform for targeted optical voltage imaging may further elucidate the mechanisms of neuronal electrical activity.