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Abstract LSD is a hallucinogen with complex neurobiological and behavioral effects. Underlying these effects are changes in brain neuroplasticity. This is the first study to follow the developmental changes in brain structure and function following LSD exposure in periadolescence. We hypothesized LSD given during a time of heightened neuroplasticity, particularly in the forebrain, would affect cognitive and emotional behavior and the associated underlying neuroanatomy and neurocircuitry. Female and male mice were given vehicle, single or multiple treatments of 3.3 µg of LSD by oral gavage starting on postnatal day 51. Between postnatal days 90–120 mice were imaged and tested for cognitive and motor behavior. MRI data from voxel-based morphometry, diffusion weighted imaging, and BOLD resting state functional connectivity were registered to a mouse 3D MRI atlas with 139 brain regions providing site-specific differences in global brain structure and functional connectivity between experimental groups. Motor behavior and cognitive performance were unaffected by periadolescent exposure to LSD. Differences across experimental groups in brain volume for any of the 139 brain areas were few in number and not focused on any specific brain region. Multiple exposures to LSD significantly altered gray matter microarchitecture across much of the brain. These changes were primary associated with the thalamus, sensory and motor cortices, and basal ganglia. The forebrain olfactory system and prefrontal cortex and hindbrain cerebellum and brainstem were unaffected. The functional connectivity between forebrain white matter tracts and sensorimotor cortices and hippocampus was reduced with multidose LSD exposure. Does exposure to LSD in late adolescence have lasting effects on brain development? The bulk of our significant findings were seen through changes is DWI values across 74 brain areas in the multi-dose LSD group. The pronounced changes in indices of anisotropy across much of the brain would suggest altered gray matter microarchitecture and neuroplasticity. There was no evidence of LSD having consequential effects on cognitive or motor behavior when animal were evaluated as young adults 90–120 days of age. Neither were there any differences in the volume of specific brain areas between experimental conditions. The reduction in connectivity in forebrain white matter tracts with multidose LSD and consolidation around sensorimotor and hippocampal brain areas requires a battery of tests to understand the consequences of these changes on behavior.

BackgroundThere are increasing reports of the misuse of prescription psychostimulants for cognitive enhancement together with recreational cannabis. This raises a concern that chronic use of cannabis high in Δ9-THC may alter the sensitivity to amphetamines. In this exploratory study we hypothesized chronic exposure to Δ9-THC through vaporized cannabis would diminish the CNS activity of Adderall.MethodsTo address this issue we exposed male and female mice to inhaled vaporized cannabis (10.3% Δ9-THC) or placebo for 30 min each day for ten consecutive days. After 24 h, mice were imaged fully awake for changes in BOLD signal following an IP injection of Adderall (60 µg) during the scanning session. After a 2-week washout, without any cannabis or placebo exposure, mice were again imaged and challenged with Adderall during the scanning session. The data were registered to a mouse 3D MRI atlas with 134 brain regions providing site-specific increases and decreases in global brain activity.ResultsMice exposed to cannabis when compared to placebo showed a decrease in brain activation to Adderall. The blunted Adderall response was characterized by a decrease in positive BOLD signal and increase in negative BOLD. The prefrontal cortex, accumbens, ventral pallidum, caudate/putamen, and thalamus were most affected. After a 2-week wash out there were no significant differences between the cannabis and placebo groups when challenged with Adderall.SummaryThis exploratory study shows that short, daily exposures to inhaled cannabis, something equivalent to recreational use, affects the sensitivity to the psychostimulant Adderall. The reduced Adderall effect on brain activity, particularly circuitry associated with dopaminergic signaling raises concerns about escalation in psychostimulant use.

Abstract A novel serotonin ligand (−)‐MBP was developed for the treatment of schizophrenia that has 5‐HT2A/2B antagonist activity together with 5‐HT2C agonist activity. The multi‐functional activity of this novel drug candidate was characterized using pharmacological magnetic resonance imaging. It was hypothesized (−)‐MBP would affect activity in brain areas associated with sensory perception. Adult male mice were given one of three doses of (−)‐MBP (3.0, 10, 18 mg/kg) or vehicle while fully awake during the MRI scanning session and imaged for 15 min post I.P. injection. BOLD functional imaging was used to follow changes in global brain activity. Data for each treatment were registered to a 3D MRI mouse brain atlas providing site‐specific information on 132 different brain areas. There was a dose‐dependent decrease in positive BOLD signal in numerous brain regions, especially thalamus, cerebrum, and limbic cortex. The 3.0 mg/kg dose had the greatest effect on positive BOLD while the 18 mg/kg dose was less effective. Conversely, the 18 mg/kg dose showed the greatest negative BOLD response while the 3.0 mg/kg showed the least. The prominent activation of the thalamus and cerebrum included the neural circuitry associated with Papez circuit of emotional experience. When compared to vehicle, the 3.0 mg dose affected all sensory modalities, for example, olfactory, somatosensory, motor, and auditory except for the visual cortex. These findings show that (−)‐MBP, a ligand with both 5‐HT2A/2B antagonist and 5‐HT2C agonist activities, interacts with thalamocortical circuitry and impacts areas involved in sensory perception.

The neurohormone oxytocin regulates many aspects of physiology primarily by binding to its receptor, the oxytocin receptor. The oxytocin receptor gene (Oxtr) has been shown to have alternative transcripts in the mouse brain which may each have different biological functions or be used in specific contexts. A popular animal model for studying oxytocin-dependent social behaviors is the prairie vole, a biparental and monogamous rodent. Alternative transcriptional capacity of Oxtr in prairie voles is unknown. We used 5′ rapid amplification of cDNA ends to identify alternative Oxtr transcription start sites in prairie vole brain tissue and uterine tissue. We then validated expression of specific transcripts in fetal brains and assessed the impact of exogenous oxytocin administration in utero on offspring brain development. We identified seven distinct Oxtr transcripts, all of which are present in both brain and uterine tissue. We then demonstrated that maternal oxytocin administration alters expression of a specific subset of Oxtr transcripts and that these different transcripts are under unique epigenetic regulation, such that in the perinatal period only one of the alternative transcripts is associated with DNA methylation in the Oxtr promoter. These data establish the existence of multiple Oxtr transcripts in prairie vole brain and uterine tissue and implicate oxytocin in the regulation of alternative transcript expression. These data have significant implications for our understanding of null mutant models in both mice and voles and translation in human birth and behavior.

BackgroundAlpha 7 nicotinic acetylcholine receptor (α7nAChR) agonists have been developed to treat schizophrenia but failed in clinical trials due to rapid desensitization. GAT107, a type 2 allosteric agonist-positive allosteric modulator (ago-PAM) to the α7 nAChR was designed to activate the α7 nAChR while reducing desensitization. We hypothesized GAT107 would alter the activity of thalamocortical neural circuitry associated with cognition, emotion, and sensory perception.MethodsThe present study used pharmacological magnetic resonance imaging (phMRI) to evaluate the dose-dependent effect of GAT107 on brain activity in awake male rats. Rats were given a vehicle or one of three different doses of GAT107 (1, 3, and 10 mg/kg) during a 35 min scanning session. Changes in BOLD signal and resting state functional connectivity were evaluated and analyzed using a rat 3D MRI atlas with 173 brain areas.ResultsGAT107 presented with an inverted-U dose response curve with the 3 mg/kg dose having the greatest effect on the positive BOLD volume of activation. The primary somatosensory cortex, prefrontal cortex, thalamus, and basal ganglia, particularly areas with efferent connections from the midbrain dopaminergic system were activated as compared to vehicle. The hippocampus, hypothalamus, amygdala, brainstem, and cerebellum showed little activation. Forty-five min post treatment with GAT107, data for resting state functional connectivity were acquired and showed a global decrease in connectivity as compared to vehicle.DiscussionGAT107 activated specific brain regions involved in cognitive control, motivation, and sensory perception using a BOLD provocation imaging protocol. However, when analyzed for resting state functional connectivity there was an inexplicable, general decrease in connectivity across all brain areas.

Abstract 1 in 20 live births in the United States is affected by prenatal alcohol exposure annually, creating a major public health crisis. The teratogenic impact of alcohol on physical growth, neurodevelopment, and behavior is extensive, together resulting in clinical disorders which fall under the umbrella term of Fetal Alcohol Spectrum Disorders (FASD). FASD-related impairments to executive function and perceptual learning are prevalent among affected youth and are linked to disruptions to corpus callosum growth and myelination in adolescence. Targeted interventions that support neurodevelopment in FASD-affected youth are nonexistent. We evaluated the capacity of an adolescent exercise intervention, a stimulator of myelinogenesis, to upregulate corpus callosum myelination in a rat model of FASD (third trimester-equivalent alcohol exposure). This study employs in vivo diffusion tensor imaging (DTI) scanning to investigate the effects of: (1) neonatal alcohol exposure and (2) an adolescent exercise intervention on corpus callosum myelination in a rodent model of FASD. DTI scans were acquired twice longitudinally (pre- and post-intervention) in male and female rats using a 9.4 Tesla Bruker Biospec scanner to assess alterations to corpus callosum myelination noninvasively. Fractional anisotropy values as well as radial/axial diffusivity values were compared within-animal in a longitudinal study design. Analyses using mixed repeated measures ANOVA’s confirm that neonatal alcohol exposure in a rodent model of FASD delays the trajectory of corpus callosum growth and myelination across adolescence, with a heightened vulnerability in the male brain. Alterations to corpus callosum volume are correlated with reductions to forebrain volume which mediates an indirect relationship between body weight gain and corpus callosum growth. While we did not observe any significant effects of voluntary aerobic exercise on corpus callosum myelination immediately after completion of the 12-day intervention, we did observe a beneficial effect of exercise intervention on corpus callosum volume growth in all rats. In line with clinical findings, we have shown that prenatal alcohol exposure leads to hypomyelination of the corpus callosum in adolescence and that the severity of damage is sexually dimorphic. Further, exercise intervention improves corpus callosum growth in alcohol-exposed and control rats in adolescence.

IntroductionThe medical and recreational use of cannabis has increased in the United States. Its chronic use can have detrimental effects on the neurobiology of the brain—effects that are age-dependent. This was an exploratory study looking at the effects of chronically inhaled vaporized cannabis on brain structure in adult female mice.MethodsAdult mice were exposed daily to vaporized cannabis (10.3% THC and 0.05% CBD) or placebo for 21 days. Following cessation of treatment mice were examined for changes in brain structure using voxel-based morphometry and diffusion weighted imaging MRI. Data from each imaging modality were registered to a 3D mouse MRI atlas with 139 brain areas.ResultsMice showed volumetric changes in the forebrain particularly the prefrontal cortex, accumbens, ventral pallidum, and limbic cortex. Many of these same brain areas showed changes in water diffusivity suggesting alterations in gray matter microarchitecture.DiscussionThese data are consistent with much of the clinical findings on cannabis use disorder. The sensitivity of the dopaminergic system to the daily exposure of vaporized cannabis raises concerns for abuse liability in drug naïve adult females that initiate chronic cannabis use.

With the recent legalization of inhaled cannabis for medicinal and recreational use, the elderly represents one of the newest, rapidly growing cohorts of cannabis users. To understand the neurobiological effects of cannabis on the aging brain, 19–20 months old mice were divided into three groups exposed to vaporized cannabis containing ~10% Δ9-THC, ~10% CBD, or placebo for 30 min each day. Voxel based morphometry, diffusion weighted imaging, and resting state functional connectivity data were gathered after 28 days of exposure and following a two-week washout period. Tail-flick, open field, and novel object preference tests were conducted to explore analgesic, anxiolytic, and cognitive effects of cannabis, respectively. Vaporized cannabis high in Δ9-THC and CBD achieved blood levels reported in human users. Mice showed antinociceptive effects to chronic Δ9-THC without tolerance while the anxiolytic and cognitive effects of Δ9-THC waned with treatment. CBD had no effect on any of the behavioral measures. Voxel based morphometry showed a decrease in midbrain dopaminergic volume to chronic Δ9-THC followed but an increase after a two-week washout. Fractional anisotropy values were reduced in the same area by chronic Δ9-THC, suggesting a reduction in gray matter volume. Cannabis high in CBD but not THC increased network strength and efficiency, an effect that persisted after washout. These data would indicate chronic use of inhaled cannabis high in Δ9-THC can be an effective analgesic but not for treatment of anxiety or cognitive decline. The dopaminergic midbrain system was sensitive to chronic Δ9-THC but not CBD showing robust plasticity in volume and water diffusivity prior to and following drug cessation an effect possibly related to the abuse liability of Δ9-THC. Chronic inhaled CBD resulted in enhanced global network connectivity that persisted after drug cessation. The behavioral consequences of this sustained change in brain connectivity remain to be determined.

Abstract Pharmacological magnetic resonance imaging (phMRI) is a noninvasive method used to evaluate neural circuitry involved in the behavioral effects of drugs like ketamine, independent of their specific biochemical mechanism. The study was designed to evaluate the immediate effect of esketamine, the S‐isomer of (±) ketamine on brain activity in awake mice using blood oxygenation level dependent (BOLD) imaging. It was hypothesized the prefrontal cortex, hippocampus, and brain areas associated with reward and motivation would show a dose‐dependent increase in brain activity. Mice were given vehicle, 1.0, 3.3, or 10 mg/kg esketamine I.P. and imaged for 10 min post‐treatment. Data for each treatment were registered to a 3D MRI mouse brain atlas providing site‐specific information on 134 different brain areas. There was a global change in brain activity for both positive and negative BOLD signal affecting over 50 brain areas. Many areas showed a dose‐dependent decrease in positive BOLD signal, for example, cortex, hippocampus, and thalamus. The most common profile when comparing the three doses was a U‐shape with the 3.3 dose having the lowest change in signal. At 1.0 mg/kg there was a significant increase in positive BOLD in forebrain areas and hippocampus. The anticipated dose‐dependent increase in BOLD was not realized; instead, the lowest dose of 1.0 mg/kg had the greatest effect on brain activity. The prefrontal cortex and hippocampus were significantly activated corroborating previous imaging studies in humans and animals. The unexpected sensitivity to the 1.0 mg/kg dose of esketamine could be explained by imaging in fully awake mice without the confound of anesthesia and/or its greater affinity for the N‐methyl‐d‐aspartate receptor (NMDAR) receptor than (±) ketamine.

Abstract Background The phytocannabinoid cannabidiol (CBD) exhibits anxiolytic activity and has been promoted as a potential treatment for post-traumatic stress disorders. How does CBD interact with the brain to alter behavior? We hypothesized that CBD would produce a dose-dependent reduction in brain activity and functional coupling in neural circuitry associated with fear and defense. Methods During the scanning session awake mice were given vehicle or CBD (3, 10, or 30 mg/kg I.P.) and imaged for 10 min post treatment. Mice were also treated with the 10 mg/kg dose of CBD and imaged 1 h later for resting state BOLD functional connectivity (rsFC). Imaging data were registered to a 3D MRI mouse atlas providing site-specific information on 138 different brain areas. Blood samples were collected for CBD measurements. Results CBD produced a dose-dependent polarization of activation along the rostral-caudal axis of the brain. The olfactory bulb and prefrontal cortex showed an increase in positive BOLD whereas the brainstem and cerebellum showed a decrease in BOLD signal. This negative BOLD affected many areas connected to the ascending reticular activating system (ARAS). The ARAS was decoupled to much of the brain but was hyperconnected to the olfactory system and prefrontal cortex. Conclusion The CBD-induced decrease in ARAS activity is consistent with an emerging literature suggesting that CBD reduces autonomic arousal under conditions of emotional and physical stress.

The clinical translation of therapeutic approaches to combat debilitating neurodegenerative conditions, such as Parkinson’s disease (PD), remains as an urgent unmet challenge. The strong molecular association between the pathogenesis of traumatic brain injury (TBI) and the development of parkinsonism in humans has been well established. Therefore, a lot of ongoing research aims to investigate this pathology overlap in-depth, to exploit the common targets of TBI and PD for development of more effective and long-term treatment strategies. This review article intends to provide a detailed background on TBI pathophysiology and its established overlap with PD with an additional emphasis on the recent findings about their effect on perivascular clearance. Although, the traditional animal models of TBI and PD are still being considered, there is a huge focus on the development of combinatory hybrid animal models coupling concussion with the pre-established PD models for a better recapitulation of the human context of PD pathogenesis. Lastly, the therapeutic targets for TBI and PD, and the contemporary research involving exosomes, DNA vaccines, miRNA, gene therapy and gene editing for the development of potential candidates are discussed, along with the recent development of lesser invasive and promising central nervous system (CNS) drug delivery strategies.

There are numerous publications on methods and applications for awake functional MRI across different species, e.g., voles, rabbits, cats, dogs, and rhesus macaques. Each of these species, most obviously rhesus monkey, have general or unique attributes that provide a better understanding of the human condition. However, much of the work today is done on rodents. The growing number of small bore (≤30 cm) high field systems 7T- 11.7T favor the use of small animals. To that point, this review is primarily focused on rodents and their many applications in awake function MRI. Applications include, pharmacological MRI, drugs of abuse, sensory evoked stimuli, brain disorders, pain, social behavior, and fear.

Breast cancer is one of the most common diseases in the United States with 1 in 8 women developing the disease in her lifetime. Women who develop breast cancer are often post-menopausal and undergo a complex sequence of treatments including surgery, chemotherapy, and aromatase inhibitor therapy. Both independently and through potential interactions, these factors and treatments are associated with behavioral comorbidities reported in patients (e.g., fatigue), although the underlying neurobiological mechanisms are poorly understood. Currently, brain imaging is the most feasible way to assess neurobiology in patients. Indeed, breast cancer patients display alterations in white matter connections and chemotherapy is associated with decreased white and gray matter in the corpus callosum and cortex as well as decreased hippocampal volume. However, imaging in breast cancer rodent models is lacking, impeding translation of the mechanistic neurobiological findings made possible through modeling. Furthermore, current rodent models of breast cancer often lack the complexity of typical multimodal breast cancer treatments, thereby limiting translational value. The present study aimed to develop a comprehensive model of post-menopausal breast cancer survival using immunocompetent ovariectomized mice, including an orthotopic syngeneic tumor, surgical tumor removal, chemotherapy, and aromatase inhibitor therapy. Using this model, we systematically investigated the cumulative effects of chemotherapy and hormone replacement therapy on neurostructure and behavior using diffusion weighted imaging, open field test, and spontaneous alternation test. Our previous findings, in a simplified chemotherapy-only model, indicate that this regimen of chemotherapy causes circulating and central inflammation concurrent with reduced locomotor activity. The current study, in the more comprehensive model, has recapitulated the peripheral inflammation coincident with reduced locomotor activity as well as demonstrated that chemotherapy also drives widespread changes in brain anisotropy. Validating the clinical relevance of this comprehensive rodent breast cancer model will allow for additional neurobiological investigations of the interactions among various cancer components associated with behavioral comorbidities, as well as the relationship between these mechanisms and neurostructural imaging changes that can be measured in cancer patients.

Abstract Background This is an exploratory study using a novel imaging modality, quantitative ultrashort time-to-echo, contrast enhanced (QUTE-CE) magnetic resonance imaging to evaluate the permeability of the blood–brain barrier in a rat model of type 2 diabetes with the presumption that small vessel disease is a contributing factor to neuropathology in diabetes. Methods The BBZDR/Wor rat, a model of type 2 diabetes, and age-matched controls were studied for changes in blood–brain barrier permeability. QUTE-CE, a quantitative vascular biomarker, generated angiographic images with over 500,000 voxels that were registered to a 3D MRI rat brain atlas providing site-specific information on blood–brain barrier permeability in 173 different brain areas. Results In this model of diabetes, without the support of insulin treatment, there was global capillary pathology with over 84% of the brain showing a significant increase in blood–brain barrier permeability over wild-type controls. Areas of the cerebellum and midbrain dopaminergic system were not significantly affected. Conclusion Small vessel disease as assessed by permeability in the blood–brain barrier in type 2 diabetes is pervasive and includes much of the brain. The increase in blood–brain barrier permeability is a likely contributing factor to diabetic encephalopathy and dementia.

Ferumoxytol, an iron oxide nanoparticle, was infused into the lateral cerebroventricle of awake rats to follow its movement and clearance from the brain using magnetic resonance imaging. Within minutes the contrast agent could be observed accumulating in the subarachnoid space, nasal cavity, nasal pharynx, and soft palate at the back of the throat. In a subsequent study fluorescent quantum dots were infused into the brain of rats and within 15 min could be observed in the esophagus using microscopy. These imaging studies clearly show that these large nanoparticle tracers (∼20 nm in diameter) leave the brain through the nasal cavity and end up in the gut. There are numerous studies going back decades reporting the clearance of tracers put directly into the brain. While these studies show the slow accumulation of trace in the blood and lymphatics, they report only accounting for less than 50% of what was originally put in the brain.

This was an exploratory study designed to evaluate the feasibility of a recently established imaging modality, quantitative ultrashort time-to-echo contrast enhanced (QUTE-CE), to follow the early pathology and vulnerability of the blood brain barrier in response to single and repetitive mild head impacts. A closed-head, momentum exchange model was used to produce three consecutive mild head impacts aimed at the forebrain separated by 24 h each. Animals were measured at baseline and within 1 h of impact. Anatomical images were collected to assess the extent of structural damage. QUTE-CE biomarkers for BBB permeability were calculated on 420,000 voxels in the brain and were registered to a bilateral 3D brain atlas providing site-specific information on 118 anatomical regions. Blood brain barrier permeability was confirmed by extravasation of labeled dextran. All head impacts occurred in the absence of any structural brain damage. A single mild head impact had measurable effects on blood brain barrier permeability and was more significant after the second and third impacts. Affected regions included the prefrontal ctx, basal ganglia, hippocampus, amygdala, and brainstem. Our findings support the concerns raised by the healthcare community regarding mild head injuries in participants in organized contact sports and military personnel in basic training and combat.

Critical studies that form the foundation of the glymphatic system and the clearance of metabolic by-products of unwanted proteins from the brain are reviewed. Concerns are raised about studying glymphatic flow in anesthetized animals and making assumptions about the whole brain based upon data collected from a cranial window on the cortex. A new model is proposed arguing that the flow of cerebral spinal fluid and parenchymal clearance in the perivascular system of unwanted proteins is regulated by circadian changes in brain temperature and blood flow at the level of the microvasculature.

Abstract Introduction Novel sensors were developed to detect exhaled volatile organic compounds to aid in the diagnosis of mild cognitive impairment associated with early stage Alzheimer's disease (AD). The sensors were sensitive to a rat model that combined the human apolipoprotein E (APOE)4 gene with aging and the Western diet. Methods Gas sensors fabricated from molecularly imprinted polymer‐graphene were engineered to react with alkanes and small fatty acids associated with lipid peroxidation. With a detection sensitivity in parts per trillion the sensors were tested against the breath of wild‐type and APOE4 male rats. Resting state BOLD functional connectivity was used to assess hippocampal function. Results Only APOE4 rats, and not wild‐type controls, tested positive to several small hydrocarbons and presented with reduced functional coupling in hippocampal circuitry. Discussion These results are proof‐of‐concept toward the development of sensors that can be used as breath detectors in the diagnosis, prognosis, and treatment of presymptomatic AD.

ObjectivesTo test the hypothesis that there are differences in neuroradiological measures between single and repeated mild traumatic brain injury using multimodal MRI.MethodsA closed-head momentum exchange model was used to produce one or three mild head injuries in young adult male rats compared to non-injured, age and weight-matched controls. Six–seven weeks post-injury, rats were studied for deficits in cognitive and motor function. Seven–eight weeks post-injury changes in brain anatomy and function were evaluated through analysis of high resolution T2 weighted images, resting-state BOLD functional connectivity, and diffusion weighted imaging with quantitative anisotropy.ResultsHead injuries occurred without skull fracture or signs of intracranial bleeding or contusion. There were no significant differences in cognitive or motors behaviors between experimental groups. With a single mild hit, the affected areas were limited to the caudate/putamen and central amygdala. Rats hit three times showed altered diffusivity in white matter tracts, basal ganglia, central amygdala, brainstem, and cerebellum. Comparing three hits to one hit showed a similar pattern of change underscoring a dose effect of repeated head injury on the brainstem and cerebellum. Disruption of functional connectivity was pronounced with three mild hits. The midbrain dopamine system, hippocampus, and brainstem/cerebellum showed hypoconnectivity. Interestingly, rats exposed to one hit showed enhanced functional connectivity (or hyperconnectivity) across brain sites, particularly between the olfactory system and the cerebellum.InterpretationNeuroradiological evidence of altered brain structure and function, particularly in striatal and midbrain dopaminergic areas, persists long after mild repetitive head injury. These changes may serve as biomarkers of neurodegeneration and risk for dementia later in life.

RNASET2 deficiency in humans is associated with infant cystic leukoencephalopathy, which causes psychomotor impairment, spasticity and epilepsy. A zebrafish mutant model suggests that loss of RNASET2 function leads to neurodegeneration due to the accumulation of non-degraded RNA in the lysosomes. The goal of this study was to characterize the first rodent model of RNASET2 deficiency. The brains of 3- and 12-month-old RNaseT2 knockout rats were studied using multiple magnetic resonance imaging modalities and behavioral tests. While T1- and T2-weighted images of RNaseT2 knockout rats exhibited no evidence of cystic lesions, the prefrontal cortex and hippocampal complex were enlarged in knockout animals. Diffusion-weighted imaging showed altered anisotropy and putative gray matter changes in the hippocampal complex of the RNaseT2 knockout rats. Immunohistochemistry for glial fibrillary acidic protein (GFAP) showed the presence of hippocampal neuroinflammation. Decreased levels of lysosome-associated membrane protein 2 (LAMP2) and elevated acid phosphatase and β-N-acetylglucosaminidase (NAG) activities indicated that the RNASET2 knockout rats likely had altered lysosomal function and potential defects in autophagy. Object recognition tests confirmed that RNaseT2 knockout rats exhibited memory deficits. However, the Barnes maze, and balance beam and rotarod tests indicated there were no differences in spatial memory or motor impairments, respectively. Overall, patients with RNASET2 deficiency exhibited a more severe neurodegeneration phenotype than was observed in the RNaseT2 knockout rats. However, the vulnerability of the knockout rat hippocampus as evidenced by neuroinflammation, altered lysosomal function and cognitive defects indicates that this is still a useful in vivo model to study RNASET2 function.

Arginine-vasopressin (AVP) plays a critical role in the regulation of offensive aggression and social status in mammals. AVP is found in an extensive neural network in the brain. Here, we discuss the role of AVP in the regulation of aggression in the limbic system with an emphasis on the critical role of hypothalamic AVP in the control of aggression. In males, activation of AVP V1a receptors (V1aRs) in the hypothalamus stimulates offensive aggression, while in females activation of V1aRs inhibits aggression. Serotonin (5-HT) also acts within the hypothalamus to modulate the effects of AVP on aggression in a sex-dependent manner. Activation of 5-HT1a receptors (5-HT1aRs) inhibits aggression in males and stimulates aggression in females. There are also striking sex differences in the mechanisms underlying the acquisition of dominance. In males, the acquisition of dominance is associated with the activation of AVP-containing neurons in the hypothalamus. By contrast, in females, the acquisition of dominance is associated with the activation of 5-HT-containing neurons in the dorsal raphe. AVP and 5-HT also play critical roles in the regulation of a form of social communication that is important for the maintenance of dominance relationships. In both male and female hamsters, AVP acts via V1aRs in the hypothalamus, as well as in other limbic structures, to communicate social status through the stimulation of a form of scent marking called flank marking. 5-HT acts on 5-HT1aRs as well as other 5-HT receptors within the hypothalamus to inhibit flank marking induced by AVP in both males and females. Interestingly, while AVP and 5-HT influence the expression of aggression in opposite ways in males and females, there are no sex differences in the effects of AVP and 5-HT on the expression of social communication. Given the profound sex differences in the incidence of many psychiatric disorders and the increasing evidence for a relationship between aggressiveness/dominance and the susceptibility to these disorders, understanding the neural regulation of aggression and social status will have significant import for translational studies.

The 5-HT6 receptor is a promising target for cognitive disorders, in particular for Alzheimer's disease (AD) and other CNS disorders. The high-affinity and selective 5-HT6 receptor antagonist idalopirdine (Lu AE58054) is currently in development for mild-moderate AD as adjunct therapy to acetylcholinesterase inhibitors (AChEIs). We studied the effects of idalopirdine alone and in combination with the AChEI donepezil on brain activity using BOLD (Blood Oxygen Level Dependent) functional magnetic resonance imaging (fMRI) in the awake rat. Idalopirdine (2 mg/kg, i.v.) alone had a modest effect on brain activity, resulting in activation of eight brain regions at the peak response. Of these, the cholinergic diagonal band of Broca, the infralimbic cortex, the ventral pallidum, the nucleus accumbens shell, and the magnocellular preoptic area were shared with the effects of donepezil (0.3 mg/kg, i.v.). Donepezil alone activated 19 brain regions at the peak response, including several cortical regions, areas of the septo-hippocampal system and the serotonergic raphe nucleus. When idalopirdine and donepezil were combined, there was a robust stimulation pattern with activation of 36 brain regions spread across the extended-amygdala-, striato-pallidal, and septo-hippocampal networks as well as the cholinergic system. These findings indicate that, whilst idalopirdine and donepezil recruit a number of overlapping regions including one of the forebrain cholinergic nuclei, the synergistic effect of both compounds extends beyond the cholinergic system and the effects of donepezil alone toward recruitment of multiple neural circuits and neurotransmitter systems. These data provide new insight into the mechanisms via which idalopirdine might improve cognition in donepezil-treated AD patients.

To evaluate brain activity associated with sexual arousal, fully conscious male marmoset monkeys were imaged during presentation of odors that naturally elicit high levels of sexual activity and sexual motivation. Male monkeys were lightly anesthetized, secured in a head and body restrainer with a built-in birdcage resonator and positioned in a 9.4-Tesla spectrometer. When fully conscious, monkeys were presented with the odors of a novel receptive female or an ovariectomized monkey. Both odors were presented during an imaging trial and the presentation of odors was counterbalanced. Significant changes in both positive and negative BOLD signal were mapped and averaged. Periovulatory odors significantly increased positive BOLD signal in several cortical areas: the striatum, hippocampus, septum, periaqueductal gray, and cerebellum, in comparison with odors from ovariectomized monkeys. Conversely, negative BOLD signal was significantly increased in the temporal cortex, cingulate cortex, putamen, hippocampus, substantia nigra, medial preoptic area, and cerebellum with presentation of odors from ovariectomized marmosets as compared to periovulatory odors. A common neural circuit comprising the temporal and cin-gulate cortices, putamen, hippocampus, medial preoptic area, and cerebellum shared both the positive BOLD response to periovulatory odors and the negative BOLD response to odors of ovariectomized females. These data suggest the odor-driven enhancement and suppression of sexual arousal affect neuronal activity in many of the same general brain areas. These areas included not only those associated with sexual activity, but also areas involved in emotional processing and reward. J. Magn. Reson. Imaging 2004;19:168–175. © 2004 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Anesthetics, widely used in magnetic resonance imaging (MRI) studies to avoid movement artifacts, could have profound effects on cerebral blood flow (CBF) and cerebrovascular coupling relative to the awake condition. Quantitative CBF and tissue oxygenation (blood oxygen level-dependent [BOLD]) were measured, using the continuous arterial-spin-labeling technique with echo-planar-imaging acquisition, in awake and anesthetized (2% isoflurane) rats under basal and hypercapnic conditions. All basal blood gases were within physiologic ranges. Blood pressure, respiration, and heart rates were within physiologic ranges in the awake condition but were depressed under anesthesia (P < 0.05). Regional CBF was heterogeneous with whole-brain CBF values of 0.86 ± 0.25 and 1.27 ± 0.29 mL · g-1 · min-1 under awake and anesthetized conditions, respectively. Surprisingly, CBF was markedly higher (20% to 70% across different brain conditions) under isoflurane-anesthetized condition compared with the awake state (P < 0.01). Hypercapnia decreased pH, and increased Pco2 and Po2. During 5% CO2 challenge, under awake and anesthetized conditions, respectively, CBF increased 51 ± 11% and 25 ± 4%, and BOLD increased 7.3 ± 0.7% and 5.4 ± 0.4%. During 10% CO2 challenge, CBF increased 158 ± 28% and 47 ± 11%, and BOLD increased 12.5 ± 0.9% and 7.2 ± 0.5%. Since CBF and BOLD responses were substantially higher under awake condition whereas blood gases were not statistically different, it was concluded that cerebrovascular reactivity was suppressed by anesthetics. This study also shows that perfusion and perfusion-based functional MRI can be performed in awake animals. [ABSTRACT FROM AUTHOR]

Unwanted proteins and metabolic waste in cerebral spinal fluid are cleared from the brain by meningeal and nasal lymphatics and the perineural sheath of cranial nerves; however, the distribution and clearance of cerebral spinal fluid (CSF) along the subarachnoid space of the entire spinal cord is not fully understood. Cryo-fluorescence tomography (CFT) was used to follow the movement of tracers from the ventricular system of the brain down through the meningeal lining of the spinal cord and out to the spinal lymphatic nodes. Isoflurane-anesthetized mice were infused into the lateral cerebroventricle with 5.0 µL of quantum dots [QdotR 605 ITKTM amino (PEG)] over two mins. Mice were allowed to recover (ca 2–3 min) and remained awake and ambulatory for 5, 15, 30, 60, and 120 min after which they were euthanized, and the entire intact body was frozen at −80°. The entire mouse was sectioned, and white light and fluorescent images were captured after each slice to produce high resolution three-dimensional volumes. Tracer appeared throughout the ventricular system and central canal of the spinal cord and the entire subarachnoid space of the CNS. A signal could be visualized in the nasal cavity, deep cervical lymph nodes, thoracic lymph nodes, and more superficial submandibular lymph nodes as early as 15 min post infusion. A fluorescent signal could be visualized along the dorsal root ganglia and down the proximal extension of the spinal nerves of the thoracic and lumbar segments at 30 min. There was a significant accumulation of tracer in the lumbar and sacral lymph nodes between 15–60 min. The dense fluorescent signal in the thoracic vertebrae noted at 5- and 15-min post infusion was significantly reduced by 30 min. Indeed, all signals in the spinal cord were ostensibly absent by 120 min, except for trace amounts in the coccyx. The brain still had some residual signal at 120 min. These data show that Qdots with a hydrodynamic diameter of 16–20 nm rapidly clear from the brain of awake mice. These data also clearly demonstrate the rapid distribution and efflux of traces along a major length of the vertebral column and the potential contribution of the spinal cord in the clearance of brain waste.

Cerebrovascular abnormality is linked to Alzheimer's disease and related dementias (ADRDs). ApoE-Ɛ4 (APOE4) is known to play a critical role in neurovascular dysfunction, however current medical imaging technologies are limited in quantification. This cross-sectional study tested the feasibility of a recently established imaging modality, quantitative ultra-short time-to-echo contrast-enhanced magnetic resonance imaging (QUTE-CE MRI), to identify small vessel abnormality early in development of human APOE4 knock-in female rat (TGRA8960) animal model. At 8 months, 48.3% of the brain volume was found to have significant signal increase (75/173 anatomically segmented regions; q

Exposure to early-life adversity (ELA) increases the risk for psychopathologies associated with amygdala-prefrontal cortex (PFC) circuits. While sex differences in vulnerability have been identified with a clear need for individualized intervention strategies, the neurobiological substrates of ELA-attributable differences remain unknown due to a paucity of translational investigations taking both development and sex into account. Male and female rats exposed to maternal separation ELA were analyzed with anterograde tracing from basolateral amygdala (BLA) to PFC to identify sex-specific innervation trajectories through juvenility (PD28) and adolescence (PD38;PD48). Resting-state functional connectivity (rsFC) was assessed longitudinally (PD28;PD48) in a separate cohort. All measures were related to anxiety-like behavior. ELA-exposed rats showed precocial maturation of BLA-PFC innervation, with females affected earlier than males. ELA also disrupted maturation of female rsFC, with enduring relationships between rsFC and anxiety-like behavior. This study is the first providing both anatomical and functional evidence for sex- and experience-dependent corticolimbic development.

Dopaminergic reward dysfunction in addictive behaviors is well supported in the literature. There is evidence that alterations in synchronous neural activity between brain regions subserving reward and various cognitive functions may significantly contribute to substance-related disorders. This study presents the first evidence showing that a pro-dopaminergic nutraceutical (KB220Z) significantly enhances, above placebo, functional connectivity between reward and cognitive brain areas in the rat. These include the nucleus accumbens, anterior cingulate gyrus, anterior thalamic nuclei, hippocampus, prelimbic and infralimbic loci. Significant functional connectivity, increased brain connectivity volume recruitment (potentially neuroplasticity), and dopaminergic functionality were found across the brain reward circuitry. Increases in functional connectivity were specific to these regions and were not broadly distributed across the brain. While these initial findings have been observed in drug naïve rodents, this robust, yet selective response implies clinical relevance for addicted individuals at risk for relapse, who show reductions in functional connectivity after protracted withdrawal. Future studies will evaluate KB220Z in animal models of addiction.

Blood oxygen level dependent (BOLD) imaging in awake mice was used to identify differences in brain activity between wild-type, and Mu (µ) opioid receptor knock-outs (MuKO) in response to oxycodone (OXY). Using a segmented, annotated MRI mouse atlas and computational analysis, patterns of integrated positive and negative BOLD activity were identified across 122 brain areas. The pattern of positive BOLD showed enhanced activation across the brain in WT mice within 15 min of intraperitoneal administration of 2.5 mg of OXY. BOLD activation was detected in 72 regions out of 122, and was most prominent in areas of high µ opioid receptor density (thalamus, ventral tegmental area, substantia nigra, caudate putamen, basal amygdala and hypothalamus), and focus on pain circuits indicated strong activation in major pain processing centers (central amygdala, solitary tract, parabrachial area, insular cortex, gigantocellularis area, ventral thalamus primary sensory cortex and prelimbic cortex). Importantly, the OXY-induced positive BOLD was eliminated in MuKO mice in most regions, with few exceptions (some cerebellar nuclei, CA3 of the hippocampus, medial amygdala and preoptic areas). This result indicates that most effects of OXY on positive BOLD are mediated by the µ opioid receptor (on-target effects). OXY also caused an increase in negative BOLD in WT mice in few regions (16 out of 122) and, unlike the positive BOLD response the negative BOLD was only partially eliminated in the MuKO mice (cerebellum), and in some case intensified (hippocampus). Negative BOLD analysis therefore shows activation and deactivation events in the absence of the µ receptor for some areas where receptor expression is normally extremely low or absent (off-target effects). Together, our approach permits establishing opioid-induced BOLD activation maps in awake mice. In addition, comparison of WT and MuKO mutant mice reveals both on-target and off-target activation events, and set an OXY brain signature that should, in the future, be compared to other µ opioid agonists.

A growing body of literature has suggested that intranasal oxytocin (OT) or other systemic routes of administration can alter prosocial behavior, presumably by directly activating OT sensitive neural circuits in the brain. Yet there is no clear evidence that OT given peripherally can cross the blood-brain-barrier at levels sufficient to engage the OT receptor. To address this issue we examined changes in blood oxygen level dependent (BOLD) signal intensity in response to peripheral OT injections (0.1, 0.5 or 2.5 mg/kg) during functional magnetic resonance (fMRI) in awake rats imaged at 7.0 tesla. These data were compared to OT (1ug/5 µl) given directly to the brain via the lateral cerebroventricle. Using a 3D annotated MRI atlas of the rat brain segmented into 171 brain areas and computational analysis we reconstructed the distributed integrated neural circuits identified with BOLD fMRI following central and peripheral OT. Both routes of administration caused significant changes in BOLD signal within the first 10 min of administration. As expected, central OT activated a majority of brain areas known to express a high density of OT receptors e.g., lateral septum, subiculum, shell of the accumbens, bed nucleus of the stria terminalis. This profile of activation was not matched by peripheral OT. The change in BOLD signal to peripheral OT did not show any discernible dose-response. Interestingly, peripheral OT affected all subdivisions of the olfactory bulb, in addition to the cerebellum and several brainstem areas relevant to the autonomic nervous system, including the solitary tract nucleus. The results from this imaging study do not support a direct central action of peripheral OT on the brain. Instead, the patterns of brain activity suggest that peripheral OT may interact at the level of the olfactory bulb and through sensory afferents from the autonomic nervous system to influence brain activity.

In the present study, we used functional MRI in awake rats to investigate the pain response that accompanies intradermal injection of capsaicin into the hindpaw. To this end, we used BOLD imaging together with a 3D segmented, annotated rat atlas and computational analysis to identify the integrated neural circuits involved in capsaicin-induced pain. The specificity of the pain response to capsaicin was tested in a transgenic model that contains a biallelic deletion of the gene encoding for the transient receptor potential cation channel subfamily V member 1 (TRPV1). Capsaicin is an exogenous ligand for the TRPV1 receptor, and in wild-type rats, activated the putative pain neural circuit. In addition, capsaicin-treated wild-type rats exhibited activation in brain regions comprising the Papez circuit and habenular system, systems that play important roles in the integration of emotional information, and learning and memory of aversive information, respectively. As expected, capsaicin administration to TRPV1-KO rats failed to elicit the robust BOLD activation pattern observed in wild-type controls. However, the intradermal injection of formalin elicited a significant activation of the putative pain pathway as represented by such areas as the anterior cingulate, somatosensory cortex, parabrachial nucleus, and periaqueductal gray. Notably, comparison of neural responses to capsaicin in wild-type versus knock-out rats uncovered evidence that capsaicin may function in an antinociceptive capacity independent of TRPV1 signaling. Our data suggest that neuroimaging of pain in awake, conscious animals has the potential to inform the neurobiological basis of full and integrated perceptions of pain.

Traumatic brain injury (TBI) can occur anywhere along the cortical mantel. While the cortical contusions may be random and disparate in their locations, the clinical outcomes are often similar and difficult to explain. Thus a question that arises is, do concussions at different sites on the cortex affect similar subcortical brain regions? To address this question we used a fluid percussion model to concuss the right caudal or rostral cortices in rats. Five days later, diffusion tensor MRI data were acquired for indices of anisotropy (IA) for use in a novel method of analysis to detect changes in gray matter microarchitecture. IA values from over 20,000 voxels were registered into a 3D segmented, annotated rat atlas covering 150 brain areas. Comparisons between left and right hemispheres revealed a small population of subcortical sites with altered IA values. Rostral and caudal concussions were of striking similarity in the impacted subcortical locations, particularly the central nucleus of the amygdala, laterodorsal thalamus, and hippocampal complex. Subsequent immunohistochemical analysis of these sites showed significant neuroinflammation. This study presents three significant findings that advance our understanding and evaluation of TBI: 1) the introduction of a new method to identify highly localized disturbances in discrete gray matter, subcortical brain nuclei without postmortem histology, 2) the use of this method to demonstrate that separate injuries to the rostral and caudal cortex produce the same subcortical, disturbances, and 3) the central nucleus of the amygdala, critical in the regulation of emotion, is vulnerable to concussion.

BOLD imaging in awake mice was used to identify differences in brain activity between wild-type, HETzQ175 and HOMzQ175 genotypes in response to the odor of almond. The study was designed to see how alterations in the huntingtin gene in a mouse model of Huntington's disease would affect the perception and processing of almond odor, an evolutionarily conserved stimulus with high emotional and motivational valence. Moreover, the mice in this study were odor naive i.e. never having smelled almond or any nuts. Using a segmented, annotated MRI atlas of the mouse and computational analysis, seventeen out of one-hundred and sixteen brain regions were identified as responding differently to almond odor across genotypes. These regions included the glomerulus of the olfactory bulb, forebrain cortex, anterior cingulate, subiculum and dentate gyrus of the hippocampus, and several areas of the hypothalamus. In many cases these regions showed a gene-dose effect with HETzQ175 mice showing a reduction in brain activity from wild-type that is further reduced in HOMzQ175 mice. Conspicuously absent were any differences in brain activity in the caudate/putamen, thalamus, CA3 and CA1 of the hippocampus and much of the cortex. The glomerulus of the olfactory bulb in HOMzQ175 mice showed a reduced change in BOLD signal intensity in response to almond odor as compared to the other phenotypes suggesting a deficit in olfactory sensitivity.