Neuroanatomical Targets Research Articles

Mapping of c-Fos Expression in Rat Brain Sub/Regions Following Chronic Social Isolation: Effective Treatments of Olanzapine, Clozapine or Fluoxetine

The c-Fos as a marker of cell activation is used to identify brain regions involved in stimuli processing. This review summarizes a pattern of c-Fos immunoreactivity and the overlapping brain sub/regions which may provide hints for the identification of neural circuits that underlie depressive- and anxiety-like behaviors of adult male rats following three and six weeks of chronic social isolation (CSIS), relative to controls, as well as the antipsychotic-like effects of olanzapine (Olz), and clozapine (Clz), and the antidepressant-like effect of fluoxetine (Flx) in CSIS relative to CSIS alone. Additionally, drug-treated controls relative to control rats were also characterized. The overlapping rat brain sub/regions with increased expression of c-Fos immunoreactivity following three or six weeks of CSIS were the retrosplenial granular cortex, c subregion, retrosplenial dysgranular cortex, dorsal dentate gyrus, paraventricular nucleus of the thalamus (posterior part, PVP), lateral/basolateral (LA/BL) complex of the amygdala, caudate putamen, and nucleus accumbens shell. Increased activity of the nucleus accumbens core following exposure of CSIS rats either to Olz, Clz, and Flx treatments was found, whereas these treatments in controls activated the LA/BL complex of the amygdala and PVP. We also outline sub/regions that might represent potential neuroanatomical targets for the aforementioned antipsychotics or antidepressant treatments.

A potential target for noninvasive neuromodulation of PTSD symptoms derived from focal brain lesions in veterans.

Neuromodulation trials for the treatment of posttraumatic stress disorder (PTSD) have yielded mixed results, and the optimal neuroanatomical target remains unclear. Here we analyzed three datasets to study brain circuitry causally linked to PTSD in military veterans. In veterans with penetrating traumatic brain injury, lesion locations that reduced probability of PTSD were preferentially connected to a circuit including the medial prefrontal cortex, amygdala and anterolateral temporal lobe. In veterans without lesions, PTSD was specifically associated with increased connectivity within this circuit. Reduced functional connectivity within this circuit after transcranial magnetic stimulation correlated with symptom reduction, even though the circuit was not directly targeted. This lesion-based 'PTSD circuit' may serve as a target for clinical trials of neuromodulation in veterans with PTSD.

Defining Overlooked Structures Reveals New Associations between the Cortex and Cognition in Aging and Alzheimer's Disease.

Recent work suggests that indentations of the cerebral cortex, or sulci, may be uniquely vulnerable to atrophy in aging and Alzheimer's disease (AD) and that the posteromedial cortex (PMC) is particularly vulnerable to atrophy and pathology accumulation. However, these studies did not consider small, shallow, and variable tertiary sulci that are located in association cortices and are often associated with human-specific aspects of cognition. Here, we manually defined 4,362 PMC sulci in 432 hemispheres in 216 human participants (50.5% female) and found that these smaller putative tertiary sulci showed more age- and AD-related thinning than larger, more consistent sulci, with the strongest effects for two newly uncovered sulci. A model-based approach relating sulcal morphology to cognition identified that a subset of these sulci was most associated with memory and executive function scores in older adults. These findings lend support to the retrogenesis hypothesis linking brain development and aging and provide new neuroanatomical targets for future studies of aging and AD.

Obesity-mediated Lipoinflammation Modulates Food Reward Responses.

Accumulation of white adipose tissue (WAT) during obesity is associated with the development of chronic low-grade inflammation, a biological process known as lipoinflammation. Systemic and central lipoinflammation accumulates pro-inflammatory cytokines including IL-6, IL-1β and TNF-α in plasma and also in brain, disrupting neurometabolism and cognitive behavior. Obesity-mediated lipoinflammation has been reported in brain regions of the mesocorticolimbic reward circuit leading to alterations in the perception and consumption of ultra-processed foods. While still under investigation, lipoinflammation targets two major outcomes of the mesocorticolimbic circuit during food reward: perception and motivation ("Wanting") and the pleasurable feeling of feeding ("Liking"). This review will provide experimental and clinical evidence supporting the contribution of obesity- or overnutrition-related lipoinflammation affecting the mesocorticolimbic reward circuit and enhancing food reward responses. We will also address neuroanatomical targets of inflammatory profiles that modulate food reward responses during obesity and describe potential cellular and molecular mechanisms of overnutrition linked to addiction-like behavior favored by brain lipoinflammation.

Prefrontal cortex melanocortin 4 receptors (MC4R) mediate food intake behavior in male mice

BackgroundMelanocortin 4 receptor (MC4R) activity in the hypothalamus is crucial for regulation of metabolism and food intake. The peptide ligands for the MC4R are associated with feeding, energy expenditure, and also with complex behaviors that orchestrate energy intake and expenditure, but the downstream neuroanatomical and neurochemical targets associated with these behaviors are elusive. In addition to strong expression in the hypothalamus, the MC4R is highly expressed in the medial prefrontal cortex, a region involved in executive function and decision-making. MethodsUsing viral techniques in genetically modified male mice combined with molecular techniques, we identify and define the effects on feeding behavior of a novel population of MC4R expressing neurons in the infralimbic (IL) region of the cortex. ResultsHere, we describe a novel population of MC4R-expressing neurons in the IL of the mouse prefrontal cortex that are glutamatergic, receive input from melanocortinergic neurons, and project to multiple regions that coordinate appetitive responses to food-related stimuli. The neurons are stimulated by application of MC4R-specific peptidergic agonist, THIQ. Deletion of MC4R from the IL neurons causes increased food intake and body weight gain and impaired executive function in simple food-related behavior tasks. ConclusionTogether, these data suggest that MC4R neurons of the IL play a critical role in the regulation of food intake in male mice.

Paraventricular thalamus controls consciousness transitions during propofol anaesthesia in mice

BackgroundThe neuronal mechanisms underlying propofol-induced modulation of consciousness are poorly understood. Neuroimaging studies suggest a potential role for non-specific thalamic nuclei in propofol-induced loss of consciousness. We investigated the contribution of the paraventricular thalamus (PVT), a midline thalamic nucleus that has been implicated in arousal control and general anaesthesia with inhaled anaesthetics, to loss and recovery of consciousness during propofol anaesthesia. MethodsPolysomnographic recordings and righting reflex test were used to determine the transitions of loss and recovery of righting reflex, used as a measure of consciousness in mice, during propofol anaesthesia in mice under conditions mimicking clinical propofol administration. PVT neuronal activities were monitored using fibre photometry and regulated using optogenetic and chemogenetic methods. ResultsPopulation activities of PVT glutamatergic neurones began to decrease before propofol-induced loss of consciousness and rapidly increased to a peak at the onset of recovery of consciousness. Chemogenetic inhibition of PVT calretinin-expressing (PVTCR) neurones shortened onset (from 176 [35] to 127 [26] s; P=0.001) and prolonged return (from 1568 [611] to 3126 [1616] s; P=0.002) of righting reflex. Conversely, chemogenetic activation of PVTCR neurones exerted opposite effects. Furthermore, optogenetic silencing of PVTCR neurones accelerated transitions to loss of consciousness (from 205 [35] to 158 [44] s; P=0.027) and slowed transitions to recovery of consciousness (from 230 [78] to 370 [99] s; P=0.041). During a steady period of unconsciousness maintained with continuous propofol infusion, brief optical activation of PVTCR neurones restored cortical activity and arousal with a latency of about 5 s. ConclusionsThe paraventricular thalamus contributes to the control of consciousness transitions in propofol anaesthesia in mice. This provides a potential neuroanatomical target for controlling consciousness to reduce anaesthetic dose requirements and side effects.

Ventral posteromedial nucleus of the thalamus as a neuroanatomical target for the anticephalalgic action of valproic acid and metamizole

Introduction. Valproic acid and metamizole are widely used in the treatment of primary headaches. However, despite the drugs’ proven clinical efficacy, the neurophysiological mechanisms underlying their therapeutic action are poorly understood. The ventral posteromedial nucleus of the thalamus (VPM) serves as the highest suprasegmental relay center for transmitting ascending nociceptive information from the cranial structures to the cerebral cortex and is considered as a potential neuroanatomical target for anticephalalgic drugs.The objective of the study was to evaluate the action of valproate and metamizole on the excitability of the VPM thalamic neurons.Methods and materials. In acute controlled experiments on anesthetized rats (n=31), we studied the action of cumulative dosing (three fixed dose injections every 30 minutes) of intravenously administered valproate (n=8, 100 mg/kg x 3) or metamizole (n=16,150 mg/kg · 3) on extracellularly recorded background and dura mater electrical stimulation-evoked activities of the convergent VPM neurons. Results. In all experiments, intravenous valproate significantly inhibited both background activity of the VPM neurons and their responses to dural electrostimulation. Metamizole had a similar action in more than half of the cases, whereas 44 % of the examined thalamic cells (7 out of 16) did not react to its infusion.Conclusion. One of the main neurophysiological mechanisms underlying anticephalalgic action of valproic acid and metamizole may be inhibition of the nociceptive transmission at the thalamic level due to the drugs-induced suppression of the meningeal-sensitive VPM neurons excitability.

Use of Three-Dimensional Printed Brain Models During Deep Brain Stimulation Surgery Consultation for Patient Health Literacy: A Randomized Controlled Investigation

Advanced therapies in neurosurgery, such as deep brain stimulation (DBS), would benefit from improved patient education materials. Three-dimensional (3D) printed anatomical models represent a recent development for improving patient education for neurosurgical procedures. In this study, 40 patients undergoing DBS surgery consultation were randomly assigned to 1 of 2 groups: an experimental group, which received a demonstration of DBS therapeutic neuroanatomical targets in a 3D printed brain model plus standard patient education (PE), or a control group, which received standard PE alone. Patients in the DBS model plus PE group showed a significant increase in patient confidence and understanding of the brain structures targeted during a DBS procedure compared with patients in the PE-only group (P < 0.01). There was no difference in perceived risk, comfort, or anxiety related to the procedure. In the first randomized controlled study to our knowledge of 3D printed models for DBS consultation, our results demonstrate that patients had improved understanding of their therapy with the models. However, the models alone did not affect risk evaluation or comfort with surgery. A 3D printed brain model may help improve patient understanding of DBS surgery.

Whole-brain activation signatures of weight-lowering drugs

ObjectiveThe development of effective anti-obesity therapeutics relies heavily on the ability to target specific brain homeostatic and hedonic mechanisms controlling body weight. To obtain further insight into neurocircuits recruited by anti-obesity drug treatment, the present study aimed to determine whole-brain activation signatures of six different weight-lowering drug classes. MethodsChow-fed C57BL/6J mice (n = 8 per group) received acute treatment with lorcaserin (7 mg/kg; i.p.), rimonabant (10 mg/kg; i.p.), bromocriptine (10 mg/kg; i.p.), sibutramine (10 mg/kg; p.o.), semaglutide (0.04 mg/kg; s.c.) or setmelanotide (4 mg/kg; s.c.). Brains were sampled two hours post-dosing and whole-brain neuronal activation patterns were analysed at single-cell resolution using c-Fos immunohistochemistry and automated quantitative three-dimensional (3D) imaging. ResultsThe whole-brain analysis comprised 308 atlas-defined mouse brain areas. To enable fast and efficient data mining, a web-based 3D imaging data viewer was developed. All weight-lowering drugs demonstrated brain-wide responses with notable similarities in c-Fos expression signatures. Overlapping c-Fos responses were detected in discrete homeostatic and non-homeostatic feeding centres located in the dorsal vagal complex and hypothalamus with concurrent activation of several limbic structures as well as the dopaminergic system. ConclusionsWhole-brain c-Fos expression signatures of various weight-lowering drug classes point to a discrete set of brain regions and neurocircuits which could represent key neuroanatomical targets for future anti-obesity therapeutics.

Intravenous doxapram administration as a potential model of panic attacks in rats.

Panic disorder can be categorized into the nonrespiratory or the respiratory subtypes, the latter comprising dyspnea, shortness of breath, chest pain, feelings of suffocation, and paresthesias. Doxapram is an analeptic capable of inducing panic attacks with respiratory symptoms in individuals diagnosed with the disorder; however, its neuroanatomical targets and its effects on experimental animals remain uncharacterized. One of the brain regions proposed to trigger panic attacks is the midbrain periaqueductal gray (PAG). Therefore, in this study, we evaluated the effects of doxapram in Fos (c-Fos) protein expression in the PAG and characterized its cardiorespiratory and behavioral effects on the elevated T maze and in the conditioned place aversion (CPA) paradigms. Doxapram increased Fos expression in different columns of the PAG, increased respiratory frequency, decreased heart rate, and increased arterial pressure when injected via intravenous route. Alprazolam, a panicolytic benzodiazepine, injected via intraperitoneal route, decreased respiratory frequency, whereas URB597, an anandamide hydrolysis inhibitor injected via intraperitoneal route, was ineffective. Doxapram injected via intraperitoneal route induced an anxiogenic-like effect in the elevated T-maze model; however, it failed to induce CPA. This study suggests that the cardiorespiratory and behavioral effects of doxapram in rodents serve as an experimental model that can provide insights into the neurobiology of panic attacks.

Focused kV X-rays for Preclinical Studies of Radiation-based Neuromodulation

Clinical observations suggest that precisely targeted irradiation can alter local neuronal function without neuronal destruction. The advancement of functional brain imaging has revealed regions of hypermetabolism that correlate with psychiatric illnesses. Radiation-based neuromodulation may offer an optimal tool to downregulate the hypermetabolic foci while preserving basic nerve functions. Achieving reliable radiomodulation in the absence of ablation, however, requires a delicate balance. Because there exists very little radiobiology information about radiomodulation and many neuroanatomical targets involved in psychiatric behaviors are believed to be similar in rodents and humans, preclinical small animal studies are critical for target identification, treatment dose planning, and treatment response evaluation. However, the target sizes in laboratory rodents are frequently below the minimum radiation field size of currently available devices. We performed Monte Carlo (MC) simulation to prove the concept of using focused kV x-ray technique to precisely deliver dose to ∼1 mm target in a rodent brain. Experiments were performed to focus 45 kVp x-rays with a polycapillary x-ray lens, which consists of a large number of small hollow curved and tapered glass tubes. The lens guides x-rays through these tubes resembling fiber optics by multiple total reflections. The x-ray transport in the lens was modeled by MC-based geometric ray tracing including defect modeling. The doses were calculated using a simulation toolkit and confirmed by phantom measurements using solid water sandwiched with films. A geometric rat brain model was created for MC treatment planning and dosimetric calculation. A focal spot size of <0.2 mm perpendicular to the beam direction can be achieved and maintained over ∼5 mm in the beam direction. The EBT3 film measured focal spot sizes and depth doses along the beam axis agree with the simulations within 10%. An example simulation was performed using multi-arc scanning for conformal irradiation to the shell region of one rat nucleus accumbens with a volume of 0.5 (LR) x 1.5 (SI) x 0.5 (AP) mm3 plus a 0.25 mm margin. The region is fundamental in brain activity related to addiction. The dose conforms to the target with fast dose fall off outside. The 70% isodose line covers 1.00 x 2.00 x 1.05 mm3. The 90% to 20% dose fall-offs are 0.2 (LR), 0.2 (SI), and 1.0 (AP) mm, respectively. AP is the depth direction of the partial arcs. Its penumbra can be improved further with arcs from more non-coplanar angles. This will also reduce the skull dose; whose current max is 47% of the prescription dose. The use of focused kV x-rays allows precise irradiation to target of just ∼1 mm without irradiating a large surrounding region, which could alter the treatment response and thus the clinical translation potential. It enables the study of radio-neuromodulation and dose volume effect to a small functional region in rat brain, which is impossible with current devices.

Neuroimaging and electrophysiology meet invasive neurostimulation for causal interrogations and modulations of brain states

Deep brain stimulation (DBS) has developed over the last twenty years into a highly effective evidenced-based treatment option for neuropsychiatric disorders. Moreover, it has become a fascinating tool to provide illustrative insights into the functioning of brain networks. New anatomical and pathophysiological models of DBS action have accelerated our understanding of neurological and psychiatric disorders and brain functioning. The description of the brain networks arose through the unique ability to illustrate long-range interactions between interconnected brain regions as derived from state-of-the-art neuroimaging (structural, diffusion, and functional MRI) and the opportunity to record local and large-scale brain activity at millisecond temporal resolution (microelectrode recordings, local field potential, electroencephalography, and magnetoencephalography).In the first part of this review, we describe how neuroimaging techniques have led to current understanding of DBS effects, by identifying and refining the DBS targets and illustrate the actual view on the relationships between electrode locations and clinical effects. One step further, we discuss how neuroimaging has shifted the view of localized DBS effects to a modulation of specific brain circuits, which has been possible from the combination of electrode location reconstructions with recently introduced network imaging methods. We highlight how these findings relate to clinical effects, thus postulating neuroimaging as a key factor to understand the mechanisms of DBS action on behavior and clinical effects. In the second part, we show how invasive electrophysiology techniques have been efficiently integrated into the DBS set-up to precisely localize the neuroanatomical targets of DBS based on distinct region-specific patterns of neural activity. Next, we show how multi-site electrophysiological recordings have granted a real-time window into the aberrant brain circuits within and beyond DBS targets to quantify and map the dynamic properties of rhythmic oscillations. We also discuss how DBS alters the transient synchrony states of oscillatory networks in temporal and spatial domains during resting, task-based and motion conditions, and how this modulation of brain states ultimately shapes the functional response. Finally, we show how a successful decoding and management of electrophysiological proxies (beta bursts, phase-amplitude coupling) of aberrant brain circuits was translated into adaptive DBS stimulation paradigms for a targeted and state-dependent invasive electrical neuromodulation.

Habenula lesions improve glucose metabolism in rats with type 2 diabetes by increasing insulin sensitivity and inhibiting gluconeogenesis

IntroductionThe habenular nucleus (Hb), a famous relay station in the midbrain, is vital for controlling many physiological functions of vertebrates. The role of Hb in the pathogenesis of depression has...

An Injectable Neural Stimulation Electrode Made from an In-Body Curing Polymer/Metal Composite.

Implanted neural stimulation and recording devices hold vast potential to treat a variety of neurological conditions, but the invasiveness, complexity, and cost of the implantation procedure greatly reduce access to an otherwise promising therapeutic approach. To address this need, a novel electrode that begins as an uncured, flowable prepolymer that can be injected around a neuroanatomical target to minimize surgical manipulation is developed. Referred to as the Injectrode, the electrode conforms to target structures forming an electrically conductive interface which is orders of magnitude less stiff than conventional neuromodulation electrodes. To validate the Injectrode, detailed electrochemical and microscopy characterization of its material properties is performed and the feasibility of using it to stimulate the nervous system electrically in rats and swine is validated. The silicone-metal-particle composite performs very similarly to pure wire of the same metal (silver) in all measures, including exhibiting a favorable cathodic charge storage capacity (CSCC ) and charge injection limits compared to the clinical LivaNova stimulation electrode and silver wire electrodes. By virtue of its simplicity, the Injectrode has the potential to be less invasive, more robust, and more cost-effective than traditional electrode designs, which could increase the adoption of neuromodulation therapies for existing and new indications.

Interventional psychiatry in the management of behavioural and psychological symptoms of dementia: a qualitative review.

&ldquo;Behavioural and psychological symptoms of dementia&rdquo; (BPSD) refers to a heterogeneous group of clinical manifestations related to dementia, including apathy, depression, anxiety, delusions, hallucinations, sexual or social disinhibition, sleep-wake cycle disturbances, aggression, agitation and other behaviours considered inappropriate. Because of the complexity and heterogeneity of BPSD, as well as the fragility and multimorbidity of the elderly, pharmacological treatment appears to be limited in terms of safety and efficacy, and nonpharmacological therapies are today considered the first choice. There is growing evidence that interventional approaches such as electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), deep brain stimulation (DBS), and vagus nerve stimulation (VNS) could be safe and efficient options for several psychiatric illnesses in a population presenting resistance to and/or intolerance of pharmacotherapy. The aim of the present work is to provide a qualitative review of the state of the art in interventional psychiatry in the treatment of BPSD. A particular focus will be on depression and agitation, which represent major stressors on caregivers and a primary cause of institutionalisation. ECT is probably the most promising interventional procedure needing further investigation in order to obtain specific protocols and a consensus on indications. Preliminary data on rTMS, tDCS, and VNS are encouraging although randomised controlled trials to investigate and compare their efficacy in the treatment of BPSD are still lacking. Their feasibility profile could represent an important advantage over ECT. DBS could represent a very effective therapy for behavioural disorders, but knowledge of the precise neuroanatomical targets for BPSD is currently too limited to justify this invasive approach.

Directional DBS leads show large deviations from their intended implantation orientation

ObjectiveLead orientation is a new degree of freedom with directional deep brain stimulation (DBS) leads. We investigated how prevalent deviations from the intended implantation direction are in a large patient cohort. MethodsThe Directional Orientation Detection (DiODe) algorithm to determine lead orientation from postoperative CT scans was implemented into the open-source Lead-DBS toolbox. Lead orientation was analyzed in 100 consecutive patients (198 leads). Different anatomical targets and intraoperative setups were compared. ResultsDeviations of up to 90° from the intended implantation direction were observed. Deviations of more than 30° were seen in 42% of the leads and deviations of more than 60° in about 11% of the leads. Deviations were independent from the neuroanatomical target and the stereotactic frame but increased depending on which microdrive was used. DiscussionOur results indicate that large deviations from the intended implantation direction are a common phenomenon in directional leads. Postoperative determination of lead orientation is thus mandatory for investigating directional DBS.

Antidepressants upregulate c-Fos expression in the lateral entorhinal cortex and hippocampal dorsal subiculum: Study in rats

Neural circuits involved in the development of depression are currently poorly understood. To provide insight into this issue, we evaluated the influence of seven clinically effective antidepressants on neuronal activity in thirty rat brain areas. Drugs belonging to all major groups of antidepressants (imipramine, reboxetine, fluoxetine, bupropion, mirtazapine, agomelatine, and phenelzine) were examined; since antidepressants typically require weeks of continued administration before they achieve a therapeutic effect, we administered these drugs for 21 days. The experiments were conducted with male Wistar rats. To identify the neuroanatomical targets for antidepressants, the alterations of c-Fos expression in different brain areas were measured using ELISA assay. The drugs were examined at doses sufficient to produce behavioral effect in the rat forced swim test (FST). All the drugs at the behaviorally relevant doses activated two brain areas, the lateral entorhinal cortex and dorsal subiculum of the hippocampus; none of the drugs affected the c-Fos expression in the medial orbital, prelimbic and infralimbic cortex, caudate putamen, nucleus accumbens core, bed nucleus of stria terminalis, hipothalamic paraventricular nucleus, medial amygdaloid nucleus, lateral habenula, substantia nigra pars compacta and pars reticulata, ventral tegmental area, hippocampal ventral subiculum, dorsal and ventral periaqueductal gray matters, and medial entorhinal cortex. These findings suggest that the stimulation of the lateral entorhinal cortex and hippocampal dorsal subiculum play a role in therapeutic effects of antidepressants.

Deep brain stimulation for cerebral palsy: where are we now?

Cerebral palsy (CP) is a complex disorder and children frequently have multiple impairments. Dystonia is a particularly frustrating impairment that interferes with rehabilitation and function and is difficult to treat. Of the available treatments, deep brain stimulation (DBS) has emerged as an option with the potential for large effect size in a subgroup of children. While brain stimulation has been used in CP for more than 40years, modern devices and targeting methods are improving both the safety and efficacy of the procedure. Successful use of DBS depends on appropriate selection of patients, identification of effective neuroanatomical targets in each patient, careful neurosurgical procedure, and detailed follow-up evaluation and programming. The use of functional neurosurgery for neuromodulation in CP remains a technology in its infancy, but improving experience and knowledge are likely to make this one of the safest and most effective interventions for children with moderate-to-severe motor disorders. This review summarizes the current procedures for patient and target selection, and surgical implantation of DBS electrodes for CP. The history of DBS and future directions when used in secondary dystonia are also examined. WHAT THIS PAPER ADDS: Selection of candidates for deep brain stimulation (DBS) requires understanding of dystonia in cerebral palsy . DBS could become a first-line treatment option in some children.

Dissociation of impulsivity and aggression in mice deficient for the ADHD risk gene Adgrl3: Evidence for dopamine transporter dysregulation

Adhesion G protein-coupled receptor L3 (ADGRL3, LPHN3) has putative roles in neuronal migration and synapse function. Various polymorphisms in ADGRL3 have been linked with an increased risk of attention deficit/hyperactivity disorder (ADHD). In this study, we examined the characteristics of Adgrl3-deficient mice in multiple behavioural domains related to ADHD: locomotive activity, impulsivity, gait, visuospatial and recognition memory, sociability, anxiety-like behaviour and aggression. Additionally, we investigated the effect of Adgrl3-depletion at the transcriptomic level by RNA-sequencing three ADHD-relevant brain regions: prefrontal cortex (PFC), hippocampus and striatum.Adgrl3−/− mice show increased locomotive activity across all tests and subtle gait abnormalities. These mice also show impairments across spatial memory and learning domains, alongside increased levels of impulsivity and sociability with decreased aggression. However, these alterations were absent in Adgrl3+/− mice. Across all brain regions tested, the numbers of genes found to exhibit differential expression was relatively small, indicating a specific pathway of action, rather than a broad neurobiological perturbation. Gene-set analysis of differential expression in the PFC detected a number of ADHD-relevant pathways including dopaminergic synapses as well as cocaine and amphetamine addiction. The Slc6a3 gene coding for the dopamine transporter was the most dysregulated gene in the PFC. Unexpectedly, several neurohormone/peptides which are typically only expressed in the hypothamalus were found to be dysregulated in the striatum. Our study further validates Adgrl3 constitutive knockout mice as an experimental model of ADHD while providing neuroanatomical targets for future studies involving ADGRL3 modified models.This article is part of the Special Issue entitled ‘Current status of the neurobiology of aggression and impulsivity’.

Distinct Neuroanatomical Structures of Acupoints Kidney 1 to Kidney 8: A Cadaveric Study.

Objective: The Systematic Classic/Zhen Jiu Jia Yi Jing (ZJJYJ, ) is considered to be the first complete acupuncture manual to detail the location and meridian assignations of 349 acupuncture points. Despite numerous transcriptions and editing changes, many traditional acupuncturists adhere to the classics and rarely question their validity. However, ushering the use of acupuncture into the modern era requires examining acupuncture point locations objectively by comparing contemporary anatomical knowledge with classical texts. The aim of this research was to examine distinct neuroanatomical targets associated with acupuncture points to: (1) standardize the precise neuroanatomical target of each acupuncture point; and (2) crossreference neuroanatomical targets with classical point locations. This was done to demonstrate ancient authors' intentions when describing acupuncture points as coordinates used to stimulate the peripheral nervous system. Materials and Methods: The unique neuroanatomical targets associated with acupuncture points on the Foot Shao Yin Kidney meridian were defined. Specifically, KI 1 through KI 8 were examined by comparing classical point locations from the ZJJYJ with modern standardized textbook locations from Chinese Acupuncture and Moxibustion, current anatomical literature, the current authors' cadaver dissection research, and electrostimulation of acupuncture points in healthy volunteers. Results: KI 1-KI 8 correlated with motor entry points as well as with nerve branches and vessels derived from the posterior tibial neurovascular bundle. Conclusions: This research demonstrated a procedure to verify and standardize the distinct neuroanatomical structures of acupuncture points. Standardization of neuroanatomical targets of acupuncture points will enable researchers and clinicians to obtain reproducible results in clinical treatments and research protocols.