ABSTRACT
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 100â 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.
ABSTRACT
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.
ABSTRACT
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.
Subject(s)
Callithrix , Prefrontal Cortex , Animals , Brain , Learning , Magnetic Resonance Imaging , Neural Pathways/physiology , Prefrontal Cortex/diagnostic imagingABSTRACT
Alcoholic liver disease (ALD), due to the multifactorial damage associated with alcohol (ethanol) consumption and metabolism, is one of the most prevalent liver diseases in the United States. The liver is the primary site of ethanol metabolism and is subsequently injured due to the production of reactive oxygen species (ROS), acetaldehyde, and metabolic stress. Building evidence suggests that dihydromyricetin (DHM), a bioactive flavonoid isolated from Hovenia dulcis, provides hepatoprotection by enhancing ethanol metabolism in the liver by maintaining hepatocellular bioenergetics, reductions of oxidative stress, and activating lipid oxidation pathways. The present study investigates the utility of DHM on hepatic mitochondrial biogenesis via activation of the AMP-activated protein kinase (AMPK)/Sirtuin (Sirt)-1/PPARG coactivator 1 (PGC)-1α signaling pathway. We utilized a forced drinking ad libitum study that chronically fed 30% ethanol to male C57BL/6J mice over 8 weeks and induced ALD pathology. We found that chronic ethanol feeding resulted in the suppression of AMPK activation and cytoplasmic Sirt-1 and mitochondrial Sirt-3 expression, effects that were reversed with daily DHM administration (5 mg/kg; intraperitoneally [i.p.]). Chronic ethanol feeding also resulted in hepatic hyperacetylation of PGC-1α, which was improved with DHM administration and its mediated increase of Sirt-1 activity. Furthermore, ethanol-fed mice were found to have increased expression of mitochondrial transcription factor A (TFAM), reduced mitochondrial content as assessed by mitochondrial DNA to nuclear DNA ratios, and significantly lower levels of hepatic ATP. In contrast, DHM administration significantly increased TFAM expression, hepatic ATP concentrations, and induced mitochondrial expression of respiratory complex III and V. In total, this work demonstrates a novel mechanism of DHM that improves hepatic bioenergetics, metabolic signaling, and mitochondrial viability, thus adding to the evidence supporting the use of DHM for treatment of ALD and other metabolic disorders.
