Spinal projecting neurons in rostral ventromedial medulla co-regulate motor and sympathetic tone.

Many behaviors require the coordinated actions of somatic and autonomic functions. However, the underlying mechanisms remain elusive. By opto-stimulating different populations of descending spinal projecting neurons (SPNs) in anesthetized mice, we show that stimulation of excitatory SPNs in the rostral ventromedial medulla (rVMM) resulted in a simultaneous increase in somatomotor and sympathetic activities. Conversely, opto-stimulation of rVMM inhibitory SPNs decreased both activities. Anatomically, these SPNs innervate both sympathetic preganglionic neurons and motor-related regions in the spinal cord. Fiber-photometry recording indicated that the activities of rVMM SPNs correlate with different levels of muscle and sympathetic tone during distinct arousal states. Inhibiting rVMM excitatory SPNs reduced basal muscle and sympathetic tone, impairing locomotion initiation and high-speed performance. In contrast, silencing the inhibitory population abolished muscle atonia and sympathetic hypoactivity during rapid eye movement (REM) sleep. Together, these results identify rVMM SPNs as descending spinal projecting pathways controlling the tone of both the somatomotor and sympathetic systems.

Cholecystokinin facilitates motor skill learning by modulating neuroplasticity in the motor cortex.

Cholecystokinin (CCK) is an essential modulator for neuroplasticity in sensory and emotional domains. Here, we investigated the role of CCK in motor learning using a single pellet reaching task in mice. Mice with a knockout of Cck gene (Cck-/-) or blockade of CCK-B receptor (CCKBR) showed defective motor learning ability; the success rate of retrieving reward remained at the baseline level compared to the wildtype mice with significantly increased success rate. We observed no long-term potentiation upon high-frequency stimulation in the motor cortex of Cck-/- mice, indicating a possible association between motor learning deficiency and neuroplasticity in the motor cortex. In vivo calcium imaging demonstrated that the deficiency of CCK signaling disrupted the refinement of population neuronal activity in the motor cortex during motor skill training. Anatomical tracing revealed direct projections from CCK-expressing neurons in the rhinal cortex to the motor cortex. Inactivation of the CCK neurons in the rhinal cortex that project to the motor cortex bilaterally using chemogenetic methods significantly suppressed motor learning, and intraperitoneal application of CCK4, a tetrapeptide CCK agonist, rescued the motor learning deficits of Cck-/- mice. In summary, our results suggest that CCK, which could be provided from the rhinal cortex, may surpport motor skill learning by modulating neuroplasticity in the motor cortex.

Dopaminergic signaling regulates microglial surveillance and adolescent plasticity in the frontal cortex.

Adolescence is a sensitive period for frontal cortical development and cognitive maturation. The dopaminergic (DA) mesofrontal circuit is particularly malleable in response to changes in adolescent experience and DA activity. However, the cellular mechanisms engaged in this plasticity remain unexplored. Here, we report that microglia, the innate immune cells of the brain, are uniquely sensitive to adolescent mesofrontal DA signaling. Longitudinal in vivo two-photon imaging in mice shows that frontal cortical microglia respond dynamically to plasticity-inducing behavioral or optogenetic DA axon stimulation with increased parenchymal and DA bouton surveillance. Microglial-axon contact precedes new bouton formation, and both D1 and D2-type DA receptors regulate microglial-bouton interactions and axonal plasticity. Moreover, D2 antagonism in adults reinstates adolescent plasticity, including increased microglial surveillance and new DA bouton formation. Our results reveal that DA signaling regulates microglial surveillance and axonal plasticity uniquely in the adolescent frontal cortex, presenting potential interventions for restoring plasticity in the adult brain.

An ethologically motivated neurobiology of primate visually-guided reach-to-grasp behavior.

The precision of primate visually guided reaching likely evolved to meet the many challenges faced by living in arboreal environments, yet much of what we know about the underlying primate brain organization derives from a set of highly constrained experimental paradigms. Here we review the role of vision to guide natural reach-to-grasp movements in marmoset monkey prey capture to illustrate the breadth and diversity of these behaviors in ethological contexts, the fast predictive nature of these movements [1,2], and the advantages of this particular primate model to investigate the underlying neural mechanisms in more naturalistic contexts [3]. In addition to their amenability to freely-moving neural recording methods for investigating the neural basis of dynamic ethological behaviors [4,5], marmosets have a smooth neocortical surface that facilitates imaging and array recordings [6,7] in all areas in the primate fronto-parietal network [8,9]. Together, this model organism offers novel opportunities to study the real-world interplay between primate vision and reach-to-grasp dynamics using ethologically motivated neuroscientific experimental designs.

Assessing the integrity of auditory sensory memory processing in CLN3 disease (Juvenile Neuronal Ceroid Lipofuscinosis (Batten disease)): an auditory evoked potential study of the duration-evoked mismatch negativity (MMN).

BACKGROUND: We interrogated auditory sensory memory capabilities in individuals with CLN3 disease (juvenile neuronal ceroid lipofuscinosis), specifically for the feature of "duration" processing. Given decrements in auditory processing abilities associated with later-stage CLN3 disease, we hypothesized that the duration-evoked mismatch negativity (MMN) of the event related potential (ERP) would be a marker of progressively atypical cortical processing in this population, with potential applicability as a brain-based biomarker in clinical trials. METHODS: We employed three stimulation rates (fast: 450 ms, medium: 900 ms, slow: 1800 ms), allowing for assessment of the sustainability of the auditory sensory memory trace. The robustness of MMN directly relates to the rate at which the regularly occurring stimulus stream is presented. As presentation rate slows, robustness of the sensory memory trace diminishes. By manipulating presentation rate, the strength of the sensory memory trace is parametrically varied, providing greater sensitivity to detect auditory cortical dysfunction. A secondary hypothesis was that duration-evoked MMN abnormalities in CLN3 disease would be more severe at slower presentation rates, resulting from greater demand on the sensory memory system. RESULTS: Data from individuals with CLN3 disease (N = 21; range 6-28 years of age) showed robust MMN responses (i.e., intact auditory sensory memory processes) at the medium stimulation rate. However, at the fastest rate, MMN was significantly reduced, and at the slowest rate, MMN was not detectable in CLN3 disease relative to neurotypical controls (N = 41; ages 6-26 years). CONCLUSIONS: Results reveal emerging insufficiencies in this critical auditory perceptual system in individuals with CLN3 disease.

Adolescent neurostimulation of dopamine circuit reverses genetic deficits in frontal cortex function.

Dopamine system dysfunction is implicated in adolescent-onset neuropsychiatric disorders. Although psychosis symptoms can be alleviated by antipsychotics, cognitive symptoms remain unresponsive and novel paradigms investigating the circuit substrates underlying cognitive deficits are critically needed. The frontal cortex and its dopaminergic input from the midbrain are implicated in cognitive functions and undergo maturational changes during adolescence. Here, we used mice carrying mutations in Arc or Disc1 to model mesofrontal dopamine circuit deficiencies and test circuit-based neurostimulation strategies to restore cognitive functions. We found that in a memory-guided spatial navigation task, frontal cortical neurons were activated coordinately at the decision-making point in wild-type but not Arc-/- mice. Chemogenetic stimulation of midbrain dopamine neurons or optogenetic stimulation of frontal cortical dopamine axons in a limited adolescent period consistently reversed genetic defects in mesofrontal innervation, task-coordinated neuronal activity, and memory-guided decision-making at adulthood. Furthermore, adolescent stimulation of dopamine neurons also reversed the same cognitive deficits in Disc1+/- mice. Our findings reveal common mesofrontal circuit alterations underlying the cognitive deficits caused by two different genes and demonstrate the feasibility of adolescent neurostimulation to reverse these circuit and behavioral deficits. These results may suggest developmental windows and circuit targets for treating cognitive deficits in neurodevelopmental disorders.

Assessing the integrity of auditory sensory memory processing in CLN3 disease (Juvenile Neuronal Ceroid Lipofuscinosis (Batten disease)): An auditory evoked potential study of the duration-evoked mismatch negativity (MMN).

Background: We interrogated auditory sensory memory capabilities in individuals with CLN3 disease (juvenile neuronal ceroid lipofuscinosis), specifically for the feature of "duration" processing, a critical cue in speech perception. Given decrements in speech and language skills associated with later-stage CLN3 disease, we hypothesized that the duration-evoked mismatch negativity (MMN) of the event related potential (ERP) would be a marker of progressively atypical cortical processing in this population, with potential applicability as a brain-based biomarker in clinical trials. Methods: We employed three stimulation rates (fast: 450 ms, medium: 900 ms, slow: 1800 ms), allowing for assessment of the sustainability of the auditory sensory memory trace. The robustness of MMN directly relates to the rate at which the regularly occurring stimulus stream is presented. As presentation rate slows, robustness of the sensory memory trace diminishes. By manipulating presentation rate, the strength of the sensory memory trace is parametrically varied, providing greater sensitivity to detect auditory cortical dysfunction. A secondary hypothesis was that duration-evoked MMN abnormalities in CLN3 disease would be more severe at slower presentation rates, resulting from greater demand on the sensory memory system. Results: Data from individuals with CLN3 disease (N=21; range 6-28 years of age) showed robust MMN responses (i.e., intact auditory sensory memory processes) at the medium stimulation rate. However, at the fastest rate, MMN was significantly reduced, and at the slowest rate, MMN was not detectable in CLN3 disease relative to neurotypical controls (N=41; ages 6-26 years). Conclusions: Results reveal emerging insufficiencies in this critical auditory perceptual system in individuals with CLN3 disease.

Increased Central Auditory Gain and Decreased Parvalbumin-Positive Cortical Interneuron Density in the Df1/+ Mouse Model of Schizophrenia Correlate With Hearing Impairment.

Background: Hearing impairment is a risk factor for schizophrenia. Patients with 22q11.2 deletion syndrome have a 25% to 30% risk of schizophrenia, and up to 60% also have varying degrees of hearing impairment, primarily from middle-ear inflammation. The Df1/+ mouse model of 22q11.2 deletion syndrome recapitulates many features of the human syndrome, including schizophrenia-relevant brain abnormalities and high interindividual variation in hearing ability. However, the relationship between brain abnormalities and hearing impairment in Df1/+ mice has not been examined. Methods: We measured auditory brainstem responses, cortical auditory evoked potentials, and/or cortical parvalbumin-positive (PV+) interneuron density in over 70 adult mice (32 Df1/+, 39 wild-type). We also performed longitudinal auditory brainstem response measurements in an additional 20 animals (13 Df1/+, 7 wild-type) from 3 weeks of age. Results: Electrophysiological markers of central auditory excitability were elevated in Df1/+ mice. PV+ interneurons, which are implicated in schizophrenia pathology, were reduced in density in the auditory cortex but not the secondary motor cortex. Both auditory brain abnormalities correlated with hearing impairment, which affected approximately 60% of adult Df1/+ mice and typically emerged before 6 weeks of age. Conclusions: In the Df1/+ mouse model of 22q11.2 deletion syndrome, abnormalities in central auditory excitability and auditory cortical PV+ immunoreactivity correlate with hearing impairment. This is the first demonstration of cortical PV+ interneuron abnormalities correlating with hearing impairment in a mouse model of either schizophrenia or middle-ear inflammation.

Fast prediction in marmoset reach-to-grasp movements for dynamic prey.

Primates have evolved sophisticated, visually guided reaching behaviors for interacting with dynamic objects, such as insects, during foraging.1,2,3,4,5 Reaching control in dynamic natural conditions requires active prediction of the target's future position to compensate for visuo-motor processing delays and to enhance online movement adjustments.6,7,8,9,10,11,12 Past reaching research in non-human primates mainly focused on seated subjects engaged in repeated ballistic arm movements to either stationary targets or targets that instantaneously change position during the movement.13,14,15,16,17 However, those approaches impose task constraints that limit the natural dynamics of reaching. A recent field study in marmoset monkeys highlights predictive aspects of visually guided reaching during insect prey capture among wild marmoset monkeys.5 To examine the complementary dynamics of similar natural behavior within a laboratory context, we developed an ecologically motivated, unrestrained reach-to-grasp task involving live crickets. We used multiple high-speed video cameras to capture the movements of common marmosets (Callithrix jacchus) and crickets stereoscopically and applied machine vision algorithms for marker-free object and hand tracking. Contrary to estimates under traditional constrained reaching paradigms, we find that reaching for dynamic targets can operate at incredibly short visuo-motor delays around 80 ms, rivaling the speeds that are typical of the oculomotor systems during closed-loop visual pursuit.18 Multivariate linear regression modeling of the kinematic relationships between the hand and cricket velocity revealed that predictions of the expected future location can compensate for visuo-motor delays during fast reaching. These results suggest a critical role of visual prediction facilitating online movement adjustments for dynamic prey.

Emotional Well-Being: What It Is and Why It Matters.

Psychological aspects of well-being are increasingly recognized and studied as fundamental components of healthy human functioning. However, this body of work is fragmented, with many different conceptualizations and terms being used (e.g., subjective well-being, psychological well-being). We describe the development of a provisional conceptualization of this form of well-being, here termed emotional well-being (EWB), leveraging prior conceptual and theoretical approaches. Our developmental process included review of related concepts and definitions from multiple disciplines, engagement with subject matter experts, consideration of essential properties across definitions, and concept mapping. Our conceptualization provides insight into key strengths and gaps in existing perspectives on this form of well-being, setting a foundation for evaluating assessment approaches, enhancing our understanding of the causes and consequences of EWB, and, ultimately, developing effective intervention strategies that promote EWB. We argue that this foundation is essential for developing a more cohesive and informative body of work on EWB. Supplementary Information: The online version contains supplementary material available at 10.1007/s42761-022-00163-0.

A Perfect Storm to Set the Stage for Ontological Exploration: Response to Commentaries on "Emotional Well-Being: What It Is and Why It Matters".

Our target article (Park et al., this issue) described the process of developing a provisional conceptualization of emotional well-being (EWB). In that article, we considered strengths and gaps in current perspectives on a variety of related concepts and ways that the proposed conceptualization of EWB informs our evaluation of measures and methods of assessment and identification of its causes and consequences. We concluded with recommendations for moving the framework and the field forward. Eight rich, thoughtful, and highly engaged commentaries addressed the target article. Collectively, these commentaries illustrate both points of consensus and areas of substantial disagreement, providing a potential roadmap for continued work. In this response, we summarize key issues raised and highlight those points raised by multiple commentators or that we considered seminal to advancing future discussion and research.

Adolescent neurostimulation of dopamine circuit reverses genetic deficits in frontal cortex function.

Dopamine system dysfunction is commonly implicated in adolescent-onset neuropsychiatric disorders. Although psychosis symptoms can be alleviated by antipsychotics, cognitive symptoms remain unresponsive to such pharmacological treatments and novel research paradigms investigating the circuit substrates underlying cognitive deficits are critically needed. The frontal cortex and its dopaminergic input from the midbrain are implicated in cognitive functions and undergo maturational changes during adolescence. Here, we used mice carrying mutations in the Arc or DISC1 genes to model mesofrontal dopamine circuit deficiencies and test circuit-based neurostimulation strategies to restore cognitive functions. We found that in a memory-guided spatial navigation task, frontal cortical neurons were activated coordinately at the decision-making point in wild-type but not Arc mutant mice. Chemogenetic stimulation of midbrain dopamine neurons or optogenetic stimulation of frontal cortical dopamine axons in a limited adolescent period consistently reversed genetic defects in mesofrontal innervation, task-coordinated neuronal activity, and memory-guided decision-making at adulthood. Furthermore, adolescent stimulation of dopamine neurons also reversed the same cognitive deficits in DISC1 mutant mice. Our findings reveal common mesofrontal circuit alterations underlying the cognitive deficits caused by two different genes and demonstrate the feasibility of adolescent neurostimulation to reverse these circuit and behavioral deficits. These results may suggest developmental windows and circuit targets for treating cognitive deficits in neurodevelopmental disorders.

A sex difference in mouse dopaminergic projections from the midbrain to basolateral amygdala.

BACKGROUND: Dopaminergic circuits play important roles in the motivational control of behavior and dysfunction in dopaminergic circuits have been implicated in several psychiatric disorders, such as schizophrenia and depression. While these disorders exhibit different incidence rates in men and women, the potential sex differences in the underlying neural circuits are not well-understood. Previous anatomical tracing studies in mammalian species have revealed a prominent circuit projection connecting the dopaminergic midbrain ventral tegmental area (VTA) to the basolateral amygdala (BLA), which is involved in emotional processing and associative learning. However, whether there is any sex difference in this anatomical circuit remains unknown. METHODS: To study the potential sex differences in the VTA-to-BLA dopaminergic circuit, we injected two viral vectors encoding fluorescent reporters of axons and synaptic boutons (AAV-FLEX-tdTomato and AAV-FLEX-SynaptophysinGFP, respectively) into the VTA of a mouse transgenic driver line (tyrosine hydroxylase promoter-driven Cre, or TH-Cre), which restricts the reporter expression to dopaminergic neurons. We then used confocal fluorescent microscopy to image the distribution and density of dopaminergic axons and synaptic boutons in serial sections of both male and female mouse brain. RESULTS: We found that the overall labeling intensity of VTA-to-BLA dopaminergic projections is intermediate among forebrain dopaminergic pathways, significantly higher than the projections to the prefrontal cortex, but lower than the projections to the nucleus accumbens. Within the amygdala areas, dopaminergic axons are concentrated in BLA. Although the size of BLA and the density of dopaminergic axons within BLA are similar between male and female mice, the density of dopaminergic synaptic boutons in BLA is significantly higher in male brain than female brain. CONCLUSIONS: Our results demonstrate an anatomical sex difference in mouse dopaminergic innervations from the VTA to BLA. This finding may provide a structural foundation to study neural circuit mechanisms underlying sex differences in motivational and emotional behaviors and related psychiatric dysfunctions.

Comparative anatomical analysis of dopamine systems in Mus musculus and Peromyscus californicus.

Dopamine plays important roles in motivational and social behaviors in mammals, and it has been implicated in several human neurological and psychiatric disorders. Rodents are used extensively as experimental models to study dopamine function in health and disease. However, interspecies differences of dopamine systems remain incompletely characterized. Here, we assessed whether the commonly referenced anatomical organization of dopamine systems in Mus musculus differs from another rodent species, Peromyscus californicus, which exhibits unique social behaviors such as biparental care. We applied tyrosine hydroxylase immunofluorescence labeling and high-throughput microscopy to establish whole-brain maps of dopamine systems in P. californicus. By comparing these maps to those from M. musculus, we identified unexpected anatomical similarity and difference between these two species. A sex difference in dopamine neurons at the anteroventral periventricular nucleus of hypothalamus, which has been implicated in regulating the maternal behaviors of the uniparental M. musculus, is similarly present in the biparental P. californicus. In contrast, major interspecies differences from M. musculus are found in the ventral midbrain and striatum of P. californicus, including the expansion of midbrain dopamine neurons into the ventral substantia nigra and the presence of an internal capsule-like white matter tract that demarcates a dorsomedial area from the rest of the striatum. These features identified in P. californicus resemble the anatomical organization of the primate brain more closely compared to those in M. musculus. Our findings suggest that P. californicus is a unique model organism for studying the evolution of dopamine systems in mammals and the disorders of dopamine systems.

Prior actions influence cost-benefit-related decision-making during mouse foraging behaviours.

Food foraging is essential for the fitness of animals. Previous studies have suggested that optimal foraging strategies involve a cost-benefit analysis comparing reward versus effort to guide action choices. Little is known how prior experience with different actions to obtain rewards may affect subsequent foraging choices. Here, we report a sunflower seed foraging test to investigate how effort and prior actions influence decision-making in laboratory mice. Sunflower seeds are a natural food favourite for mice, and mice spend effort to peel the hard shells to obtain the seeds. In our test, peeled and unpeeled sunflower seeds were placed at different ends of a Y-maze. Mice were free to explore the maze and make foraging decisions. Naïve mice were more likely to choose peeled seeds requiring low effort versus unpeeled seeds requiring high effort. Furthermore, mice with prior seed peeling experience significantly reduced preference for peeled seeds during the subsequent Y-maze foraging test, compared with mice pre-exposed to peeled seeds only. This experience-dependent shift in foraging choice was associated with reduced seed peeling time and improved motor skills with practice, and predictable on a trial-by-trial basis by a probabilistic decision-making model with the amount of peeled and unpeeled seeds consumed as inputs. Together, these results suggest that laboratory mice make rational foraging choices based on effort estimation and moreover, prior actions to obtain reward alter effort estimation and decision-making through motor skill learning. This naturalist behavioural task may be applied to dissect neural mechanisms in adaptive decision-making during foraging.

Effect of short-term high temperature on the accumulation of glucosinolates in Brassica rapa.

Glucosinolates, an important class of secondary metabolites in cruciferous vegetables, play a crucial role in protecting plants from stress-related damage. The mechanism of glucosinolate synthesis under short-term high temperature stress has not been sufficiently studied. In this work, we investigated the changes in transcription factors, synthetic genes, and related metabolites involved in glucosinolate synthesis by pakchoi seedlings under short-term high temperature stress (40 °C for 8 h). Short-term high temperature stress inhibited the primary sulfur assimilation and the contents of methionine, cysteine and glutathione. The contents of aliphatic and indolic glucosinolates were increased by short-term high temperature stress, whereas the content of 4-methoxy-glucobrassicin increased significantly. During the stress period, the transcript level of glucosinolate related MYB transcription factors had been basically significantly up-regulated, whereas the transcript level of aliphatic and indolic glucosinolate synthetic genes were predominantly up-regulated and down-regulated respectively. In the early recovery period, primary sulfur assimilation up-regulated rapidly, and decreased during the late recovery process. The glucosinolate content and synthesis gene expression act similar to the primary sulfur assimilation, a short up-regulated in early recovery, then all go down at 40 and 48 h after short-term high temperature treatment.

KCNH2-3.1 mediates aberrant complement activation and impaired hippocampal-medial prefrontal circuitry associated with working memory deficits.

Increased expression of the 3.1 isoform of the KCNH2 potassium channel has been associated with cognitive dysfunction and with schizophrenia, yet little is known about the underlying pathophysiological mechanisms. Here, by using in vivo wireless local field potential recordings during working memory processing, in vitro brain slice whole-cell patching recordings and in vivo stereotaxic hippocampal injection of AAV-encoded expression, we identified specific and delayed disruption of hippocampal-mPFC synaptic transmission and functional connectivity associated with reductions of SERPING1, CFH, and CD74 in the KCNH2-3.1 overexpression transgenic mice. The differentially expressed genes in mice are enriched in neurons and microglia, and reduced expression of these genes dysregulates the complement cascade, which has been previously linked to synaptic plasticity. We find that knockdown of these genes in primary neuronal-microglial cocultures from KCNH2-3.1 mice impairs synapse formation, and replenishing reduced CFH gene expression rescues KCNH2-3.1-induced impaired synaptogenesis. Translating to humans, we find analogous dysfunctional interactions between hippocampus and prefrontal cortex in coupling of the fMRI blood oxygen level-dependent (BOLD) signal during working memory in healthy subjects carrying alleles associated with increased KCNH2-3.1 expression in brain. Our data uncover a previously unrecognized role of the truncated KCNH2-3.1 potassium channel in mediating complement activation, which may explain its association with altered hippocampal-prefrontal connectivity and synaptic function. These results provide a potential molecular link between increased KCNH2-3.1 expression, synapse alterations, and hippocampal-prefrontal circuit abnormalities implicated in schizophrenia.

Developmental Exposure to Psychostimulant Primes Activity-dependent Gene Induction in Frontal Cortex.

Perinatal neurodevelopment involves extensive formation of neural connections and onset of activity-dependent gene expression for synaptic function and plasticity. Exposure to psychostimulants at this stage imposes significant risks for developing cognitive and affective disorders later in life. However, how developmental exposure to psychostimulants may induce long-lasting molecular changes relevant to neural circuit function remains incompletely understood. In this study, we investigated the impacts of psychostimulant amphetamine on the activity-dependent induction of synaptic adaptor molecule Arc in the frontal cortex of neonatal mice. We found that transient exposure to amphetamine not only amplifies activity-dependent Arc mRNA expression immediately, but also potentiates subsequent induction of Arc mRNA in the absence of amphetamine. This priming effect is associated with a rapid and persistent increase in histone mono-methylation (H3K4me1), a marker for transcriptionally permissive chromatin, at the Arc locus, but not any long-lasting change in the phosphorylation of upstream transcription factor CREB. Furthermore, the increase in H3K4me1 at the Arc locus requires dopamine receptor signaling, and the priming of Arc expression correlates with the dopaminergic innervation pattern in the frontal cortex. Together, our results demonstrate that developmental exposure to psychostimulant amphetamine induces long-lasting chromatin changes and primes activity-dependent Arc gene induction. These findings reveal the molecular targets of psychostimulant during perinatal development that may contribute to long-term psychiatric risks.