Dose-dependent LSD effects on cortical/thalamic and cerebellar activity: brain oxygen level-dependent fMRI study in awake rats.

Lysergic acid diethylamide is a hallucinogen with complex neurobiological and behavioural effects. This is the first study to use MRI to follow functional changes in brain activity in response to different doses of lysergic acid diethylamide in fully awake, drug-naive rats. We hypothesized that lysergic acid diethylamide would show a dose-dependent increase in activity in the prefrontal cortex and thalamus while decreasing hippocampal activity. Female and male rats were given intraperitoneal injections of vehicle or lysergic acid diethylamide in doses of 10 or 100 µg/kg while fully awake during the imaging session. Changes in blood oxygen level-dependent signal were recorded over a 30-min window. Approximately 45-min post-injection data for resting-state functional connectivity were collected. All data were registered to rat 3D MRI atlas with 173 brain regions providing site-specific increases and decreases in global brain activity and changes in functional connectivity. Treatment with lysergic acid diethylamide resulted in a significant dose-dependent increase in negative blood oxygen level-dependent signal. The areas most affected were the primary olfactory system, prefrontal cortex, thalamus and hippocampus. This was observed in both the number of voxels affected in these brains regions and the changes in blood oxygen level-dependent signal over time. However, there was a significant increase in functional connectivity between the thalamus and somatosensory cortex and the cerebellar nuclei and the surrounding brainstem areas. Contrary to our hypothesis, there was an acute dose-dependent increase in negative blood oxygen level-dependent signal that can be interpreted as a decrease in brain activity, a finding that agrees with much of the behavioural data from preclinical studies. The enhanced connectivity between thalamus and sensorimotor cortices is consistent with the human literature looking at lysergic acid diethylamide treatments in healthy human volunteers. The unexpected finding that lysergic acid diethylamide enhances connectivity to the cerebellar nuclei raises an interesting question concerning the role of this brain region in the psychotomimetic effects of hallucinogens.

Dose-dependent effects of GAT107, a novel allosteric agonist-positive allosteric modulator (ago-PAM) for the α7 nicotinic cholinergic receptor: a BOLD phMRI and connectivity study on awake rats.

Background: Alpha 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. Methods: The 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. Results: GAT107 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. Discussion: GAT107 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.

Effects of inhaled cannabis high in Δ9-THC or CBD on the aging brain: A translational MRI and behavioral study.

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.

Neuroanatomical and functional consequences of oxytocin treatment at birth in prairie voles.

Birth is a critical period for the developing brain, a time when surging hormone levels help prepare the fetal brain for the tremendous physiological changes it must accomplish upon entry into the 'extrauterine world'. A number of obstetrical conditions warrant manipulations of these hormones at the time of birth, but we know little of their possible consequences on the developing brain. One of the most notable birth signaling hormones is oxytocin, which is administered to roughly 50% of laboring women in the United States prior to / during delivery. Previously, we found evidence for behavioral, epigenetic, and neuroendocrine consequences in adult prairie vole offspring following maternal oxytocin treatment immediately prior to birth. Here, we examined the neurodevelopmental consequences in adult prairie vole offspring following maternal oxytocin treatment prior to birth. Control prairie voles and those exposed to 0.25 mg/kg oxytocin were scanned as adults using anatomical and functional MRI, with neuroanatomy and brain function analyzed as voxel-based morphometry and resting state functional connectivity, respectively. Overall, anatomical differences brought on by oxytocin treatment, while widespread, were generally small, while differences in functional connectivity, particularly among oxytocin-exposed males, were larger. Analyses of functional connectivity based in graph theory revealed that oxytocin-exposed males in particular showed markedly increased connectivity throughout the brain and across several parameters, including closeness and degree. These results are interpreted in the context of the organizational effects of oxytocin exposure in early life and these findings add to a growing literature on how the perinatal brain is sensitive to hormonal manipulations at birth.

Structural and functional variations in the prefrontal cortex are associated with learning in pre-adolescent common marmosets (Callithrix jacchus).

There is substantial evidence linking the prefrontal cortex (PFC) to a variety of cognitive abilities, with adolescence being a critical period in its development. In the current study, we investigated the neural basis of differences in learning in pre-adolescent common marmosets. At 8 months old, marmosets were given anatomical and resting state MRI scans (n = 24). At 9 months old, association learning and inhibitory control was tested using a 'go/no go' visual discrimination (VD) task. Marmosets were grouped into 'learners' (n = 12) and "non-learners" (n = 12), and associations between cognitive performance and sub-regional PFC volumes, as well as PFC connectivity patterns, were investigated. "Learners" had significantly (p < 0.05) larger volumes of areas 11, 25, 47 and 32 than 'non-learners', although 'non-learners' had significantly larger volumes of areas 24a and 8 v than "learners". There was also a significant correlation between average % correct responses to the 'punished' stimulus and volume of area 47. Further, 'non-learners' had significantly greater global PFC connections, as well as significantly greater numbers of connections between the PFC and basal ganglia, cerebellum and hippocampus, compared to 'learners'. These results suggest that larger sub-regions of the orbitofrontal cortex and ventromedial PFC, as well more refined PFC connectivity patterns to other brain regions associated with learning, may be important in successful response inhibition. This study therefore offers new information on the neurodevelopment of individual differences in cognition during pre-adolescence in non-human primates.

Changes in brain structure and function following chronic exposure to inhaled vaporised cannabis during periadolescence in female and male mice: A multimodal MRI study.

BACKGROUND AND AIMS: Social norms and legality surrounding the use of medical and recreational cannabis are changing rapidly. The prevalence of cannabis use in adolescence is increasing. The aim of this study was to assess any sex-based neurobiological effects of chronically inhaled, vaporised cannabis on adolescent female and male mice. METHODS: Female and male mice were exposed daily to vaporised cannabis (10.3% Δ-9-tetrahydrocannabinol [THC] and 0.05% cannabidiol [CBD]) or placebo from postnatal day 23 to day 51. Following cessation of treatment, mice were examined for changes in brain structure and function using noninvasive multimodal magnetic resonance imaging (MRI). Data from voxel-based morphometry, diffusion weighted imaging and rest state functional connectivity were registered to and analysed with a 3D mouse atlas with 139 brain areas. Following imaging, mice were tested for their preference for a novel object. RESULTS: The effects were sexually dimorphic with females showing a unique distribution and inverse correlation between measures of fractional anisotropy and apparent diffusion coefficient localised to the forebrain and hindbrain. In contrast males displayed significant increased functional coupling with the thalamus, hypothalamus and brainstem reticular activating system as compared with controls. Cannabis males also presented with altered hippocampal coupling and deficits in cognitive function. CONCLUSION: Chronic exposure to inhaled vaporised cannabis had significant effects on brain structure and function in early adulthood corroborating much of the literature. Females presented with changes in grey matter microarchitecture, while males showed altered functional connectivity in hippocampal circuitry and deficits in object recognition.

Differences in Diffusion-Weighted Imaging and Resting-State Functional Connectivity Between Two Culturally Distinct Populations of Prairie Vole.

BACKGROUND: We used the highly prosocial prairie vole to test the hypothesis that higher-order brain structure-microarchitecture and functional connectivity (FC)-would differ between males from populations with distinctly different levels of prosocial behavior. Specifically, we studied males from Illinois (IL), which display high levels of prosocial behavior, and first generation males from Kansas dams and IL males (KI), which display the lowest level of prosocial behavior and higher aggression. Behavioral differences between these males are associated with overexpression of estrogen receptor alpha in the medial amygdala and bed nucleus of the stria terminalis and neuropeptide expression in the paraventricular nucleus. METHODS: We compared apparent diffusion coefficient, fractional anisotropy, and blood oxygen level-dependent resting-state FC between males. RESULTS: IL males displayed higher apparent diffusion coefficient in regions associated with prosocial behavior, including the bed nucleus of the stria terminalis, paraventricular nucleus, and anterior thalamic nuclei, while KI males showed higher apparent diffusion coefficient in the brainstem. KI males showed significantly higher fractional anisotropy than IL males in 26 brain regions, with the majority being in the brainstem reticular activating system. IL males showed more blood oxygen level-dependent resting-state FC between the bed nucleus of the stria terminalis, paraventricular nucleus, and medial amygdala along with other brain regions, including the hippocampus and areas associated with social and reward networks. CONCLUSIONS: Our results suggest that gray matter microarchitecture and FC may play a role the expression of prosocial behavior and that differences in other brain regions, especially the brainstem, could be involved. The differences between males suggests that this system represents a potentially valuable model system for studying emotional differences and vulnerability to stress and addiction.

Functional Connectivity Differences Between Two Culturally Distinct Prairie Vole Populations: Insights Into the Prosocial Network.

BACKGROUND: The goal of this study was to elucidate the fundamental connectivity-resting-state connectivity-within and between nodes in the olfactory and prosocial (PS) cores, which permits the expression of social monogamy in males; and how differential connectivity accounts for differential expression of prosociality and aggression. METHODS: Using resting-state functional magnetic resonance imaging, we integrated graph theory analysis to compare functional connectivity between two culturally/behaviorally distinct male prairie voles (Microtusochrogaster). RESULTS: Illinois males display significantly higher levels of prosocial behavior and lower levels of aggression than KI (Kansas dam and Illinois sire) males, which are associated with differences in underlying neural mechanisms and brain microarchitecture. Shared connectivity 1) between the anterior hypothalamic area and the paraventricular nucleus and 2) between the medial preoptic area and bed nucleus of the stria terminalis and the nucleus accumbens core suggests essential relationships required for male prosocial behavior. In contrast, Illinois males displayed higher levels of global connectivity and PS intracore connectivity, a greater role for the bed nucleus of the stria terminalis and anterior hypothalamic area, which were degree connectivity hubs, and greater PS and olfactory intercore connectivity. CONCLUSIONS: These findings suggest that behavioral differences are associated with PS core degree of connectivity and postsignal induction. This transgenerational system may serve as powerful mental health and drug abuse translational model in future studies.

Exposure to methylphenidate during peri-adolescence decouples the prefrontal cortex: a multimodal MRI study.

This study was designed to assess the effects of daily psychostimulant exposure during juvenility and peri-adolescence on brain morphology and functional connectivity using multimodal magnetic resonance imaging. We hypothesized that long-term exposure to methylphenidate would enhance connectivity with the prefrontal cortex. Male rats were given daily injections of either methylphenidate (n=10), dextroamphetamine (n=10) or saline vehicle (n=10) from postnatal day 21 to 42. They were imaged between postnatal day 43 and 48. Voxel-based morphometry, diffusion weighted imaging, and resting state functional connectivity were used to quantify brain structure and function. Images from each modality were registered and analyzed, using a 3D MRI rat atlas providing site-specific data over 171 different brain areas. Following imaging, rats were tested for cognitive function using novel object preference. Long-lasting psychostimulant treatment was associated with only a few significant changes in brain volume and measures of anisotropy compared to vehicle. Resting state functional connectivity imaging revealed decreased coupling between the prefrontal cortex, basal ganglia and sensory motor cortices. There were no significant differences between experimental groups for cognitive behavior. In this exploratory study, we showed that chronic psychostimulant treatment throughout juvenility and preadolescence has a minimal effect on brain volume and gray matter microarchitecture, but significantly uncouples the connectivity in the cerebral/basal ganglia circuitry.

Cannabidiol has a unique effect on global brain activity: a pharmacological, functional MRI study in awake mice.

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.

Effects of methamphetamine on alloparental behavior in male and female prairie voles.

Psychostimulant abuse is associated with a variety of impairments in social functioning, including an increased frequency of depression and aggression and deficits in social cognition. Psychostimulants reduce social investigation in rats and mice; however, it is less clear how other forms of social behavior (e.g., prosocial behavior) are affected. Females are also generally more sensitive to the effects of psychostimulants on locomotion and stereotyped behavior, which suggests that females might also display greater disruption of prosocial behavior. In order to test the hypothesis that psychostimulants reduce prosocial behavior and that females are more vulnerable, we treated adult male and female prairie voles with methamphetamine for three days (0, 0.2 or 2.0mg/kg, i.p.) and examined effects on locomotion and alloparental behavior. The lower methamphetamine dose increased activity in the open field in males and reduced locomotion in females. Methamphetamine-treated males took longer to enter the pup chamber, but both sexes displayed reduced pup contact following treatment with the lower methamphetamine dose. The methamphetamine-induced reduction in prosocial behavior was not associated with changes in pup-directed aggression in males or females. In order to investigate potential mechanisms underlying these changes in behavior, we measured adrenal weights as a proxy for activation of the hypothalamic-pituitary-adrenal (HPA) axis. The higher methamphetamine dose increased adrenal weights. Collectively, these data demonstrate that methamphetamine administration reduces alloparental behavior in both sexes and that females are more sensitive to some of the effects of this drug (e.g., locomotion/stereotyped behavior and possibly stimulation of the HPA axis).

Microarray analysis of aging-associated immune system alterations in the rostral ventrolateral medulla of F344 rats.

The rostral ventrolateral medulla (RVLM) is an area of the brain stem that contains diverse neural substrates that are involved in systems critical for physiological function. There is evidence that aging affects some neural substrates within the RVLM, although age-related changes in RVLM molecular mechanisms are not well established. The goal of the present study was to characterize the transcriptomic profile of the aging RVLM and to test the hypothesis that aging is associated with altered gene expression in the RVLM, with an emphasis on immune system associated gene transcripts. RVLM tissue punches from young, middle-aged, and aged F344 rats were analyzed with Agilent's whole rat genome microarray. The RVLM gene expression profile varied with age, and an association between chronological age and specific RVLM gene expression patterns was observed [P < 0.05, false discovery rate (FDR) < 0.3]. Functional analysis of RVLM microarray data via gene ontology profiling and pathway analysis identified upregulation of genes associated with immune- and stress-related responses and downregulation of genes associated with lipid biosynthesis and neurotransmission in aged compared with middle-aged and young rats. Differentially expressed genes associated with the complement system and microglial cells were further validated by quantitative PCR with separate RVLM samples (P < 0.05, FDR < 0.1). The present results have identified age-related changes in the transcriptomic profile of the RVLM, modifications that may provide the molecular backdrop for understanding age-dependent changes in physiological regulation.

Development of an ethanol model using social insects: II. Effect of Antabuse on consumatory responses and learned behavior of the honey bee (Apis mellifera L.).

The ability of Antabuse (disulfiram) to influence ethanol consumption and learning in harnessed honey bees was investigated. In the first series of experiments a factorial design was used with 5 levels of ethanol concentration (0%, 1%, 5%, 10%, 20%), 4 doses of Antabuse (0, 37 microg/g, 3.7 microg/g, .37 microg/g), and 2 testing intervals (1 min., 10 min.). Animals were fed a single 1 microl dose of Antabuse and contact time with an ethanol solution measured. A second series of experiments investigated the influence of Antabuse on the formation of Pavlovian conditioning of the proboscis extension reflex. A factorial design was used with two levels of training (paired, unpaired), three levels of ethanol (0%, 1%, 5%), and 2 levels of pretreatment (distilled water, 3.7 microg/g). Analysis of the consumption experiments indicate that pretreatment with Antabuse reduces ethanol intake, although there was substantial variability. The findings of the Pavlovian experiments suggest that pretreatment with Antabuse significantly reduced responding to a CS signaling the availability of ethanol.

Neurorrafias-evaluación cinco años después / Neurorraphias-evaluation five years later

El presente papel tiene como objetivo estudiar y analizar los resultados obtenidos en la reparación de nervios periféricos, a largo plazo, en el presente caso, 5 años después de la reparación del tronco nervioso seccionado, con técnicas de sutura convencional y la utilización de la cola de fibrina como sutura del mismo efecto. Observando resultados muy similares en ambos grupos, con dificultad para una fuerza muscular buena (hecho frecuente en estas lesiones), pero con una recuperación sensitiva aceptable