Role of the anterior cingulate cortex in the retrieval of novel object recognition memory after a long delay

Previous in vivo electrophysiological studies suggest that the anterior cingulate cortex (ACgx) is an important substrate of novel object recognition (NOR) memory. However, intervention studies are needed to confirm this conclusion and permanent lesion studies cannot distinguish effects on encoding and retrieval. The interval between encoding and retrieval tests may also be a critical determinant of the role of the ACgx. The current series of experiments used micro-infusion of the GABAA receptor agonist, muscimol, into ACgx to reversibly inactivate the area and distinguish its role in encoding and retrieval. ACgx infusions of muscimol, before encoding did not alter NOR assessed after a delay of 20 min or 24 h. However, when infused into the ACgx before retrieval muscimol impaired NOR assessed after a delay of 24 h, but not after a 20 min retention test. Together these findings suggest that the ACgx plays a time-dependent role in the retrieval, but not the encoding, of NOR memory, neuronal activation being required for the retrieval of remote (24 h old), but not recent (20 min old) visual memory

Scopolamine impairs appetitive but not aversive trace conditioning: role of the medial prefrontal cortex

The muscarinic acetylcholine (ACh) receptor is an important modulator of medial prefrontal cortex (mPFC) functions, such as the working memory required to bridge a trace interval in associative leaning. Aversive and appetitive trace conditioning procedures were used to examine the effects of scopolamine (0.1 and 0.5 mg/kg i.p.) in male rats. Follow-up experiments tested the effects of microinfusion of 0.15 ?g scopolamine (0.075 ?g in 0.5 ?L/side) in infralimbic (IL) versus prelimbic (PL) regions of rat mPFC, in appetitive trace and locomotor activity (LMA) procedures. Systemic scopolamine was without effect in an aversive trace conditioning procedure but impaired appetitive conditioning at a 2 s trace interval. This effect was demonstrated as reduced responding during presentations of the conditioned stimulus (CS) as well as during the inter-stimulus-interval (ISI). There was no such effect on responding during food (unconditioned stimulus, US) responding or in the inter-trial-interval (ITI). In contrast, systemic scopolamine dose-relatedly increased LMA. Trace conditioning was similarly impaired at the 2 s trace (shown as reduced responding to the CS and during the ISI, but not during US presentations or in the ITI) after infusion in mPFC, whilst LMA was increased (after infusion in IL only). Thus, results point to the importance of cholinergic modulation in mPFC for trace conditioning and show that the observed effects cannot be attributed to reduced activity

Traumatic brain injuries and problem gambling in youth: Evidence from a population-based study of secondary students in Ontario, Canada

Traumatic brain injury (TBI) is characterized by a change in brain function after an external force or sudden movement to the head. TBI is associated with risk-taking, impulsivity, psychological distress, substance abuse, and violent crime. Previous studies have also linked problem gambling to TBI, but these studies have not controlled for possible confounding variables such as mental health problems and hazardous drinking which are also linked to TBI. This study examines the relationship between problem gambling and TBI among adolescents. Data were obtained from the 2011, 2013 and 2015 cycles of the OSDUHS, a biennial cross-sectional school-based study of children in grades 7 to 12 (N = 9,198). Logistic regression was used to estimate adjusted odds ratios (AOR) in controlled and uncontrolled analyses. Adjusting for sex and grade only, problem gambling was associated with a history of TBI (AOR = 2.8). This association remained significant after adjusting for hazardous drinking and suicidality (AOR = 2.0). In addition, problem gambling had a statistically significant relationship with being male (AOR = 4.7), hazardous drinking (AOR = 4.5), and suicidality (AOR = 3.1). This study provides further data to suggest a link between TBI and problem gambling. However, research is needed on the causal relationship between these variables and the potential implications for treatment and prevention

Whole-body and adipose tissue-specific mechanisms underlying the metabolic effects of fibroblast growth factor 21 in the Siberian hamster.

OBJECTIVE: Fibroblast growth factor 21 (FGF21) has been shown to rapidly lower body weight in the Siberian hamster, a preclinical model of adiposity. This induced negative energy balance mediated by FGF21 is associated with both lowered caloric intake and increased energy expenditure. Previous research demonstrated that adipose tissue (AT) is one of the primary sites of FGF21 action and may be responsible for its ability to increase the whole-body metabolic rate. The present study sought to determine the relative importance of white (subcutaneous AT [sWAT] and visceral AT [vWAT]), and brown (interscapular brown AT [iBAT]) in governing FGF21-mediated metabolic improvements using the tissue-specific uptake of glucose and lipids as a proxy for metabolic activity. METHODS: We used positron emission tomography-computed tomography (PET-CT) imaging in combination with both glucose (18F-fluorodeoxyglucose) and lipid (18F-4-thiapalmitate) tracers to assess the effect of FGF21 on the tissue-specific uptake of these metabolites and compared responses to a control group pair-fed to match the food intake of the FGF21-treated group. In vivo imaging was combined with ex vivo tissue-specific functional, biochemical, and molecular analyses of the nutrient uptake and signaling pathways. RESULTS: Consistent with previous findings, FGF21 reduced body weight via reduced caloric intake and increased energy expenditure in the Siberian hamster. PET-CT studies demonstrated that FGF21 increased the uptake of glucose in BAT and WAT independently of reduced food intake and body weight as demonstrated by imaging of the pair-fed group. Furthermore, FGF21 increased glucose uptake in the primary adipocytes, confirming that these in vivo effects may be due to a direct action of FGF21 at the level of the adipocytes. Mechanistically, the effects of FGF21 are associated with activation of the ERK signaling pathway and upregulation of GLUT4 protein content in all fat depots. In response to treatment with FGF21, we observed an increase in the markers of lipolysis and lipogenesis in both the subcutaneous and visceral WAT depots. In contrast, FGF21 was only able to directly increase the uptake of lipid into BAT. CONCLUSIONS: These data identify brown and white fat depots as primary peripheral sites of action of FGF21 in promoting glucose uptake and also indicate that FGF21 selectively stimulates lipid uptake in brown fat, which may fuel thermogenesis

Photoperiodic changes in adiposity increase sensitivity of female Siberian hamsters to systemic VGF derived peptide TLQP-21

TLQP-21, a peptide encoded by the highly conserved vgf gene, is expressed in neuroendocrine cells and has been the most prominent VGF-derived peptide studied in relation to control of energy balance. The recent discovery that TLQP-21 is the natural agonist for the complement 3a receptor 1 (C3aR1) has revived interest in this peptide as a potential drug target for obesity. We have investigated its function in Siberian hamsters (Phodopus sungorus), a rodent that displays natural seasonal changes in body weight and adiposity as an adaptation to survive winter. We have previously shown that intracerebroventricular administration of TLQP-21 reduced food intake and body weight in hamsters in their long-day fat state. The aim of our current study was to determine the systemic actions of TLQP-21 on food intake, energy expenditure and body weight, and to establish whether adiposity affected these responses. Peripheral infusion of TLQP-21 (1mg/kg/day for 7 days) in lean hamsters exposed to short photoperiods (SP) reduced cumulative food intake in the home cage (p≤0.05), and intake when measured in metabolic cages (P≤0.01). Energy expenditure was significantly increased (

Moderate to severe gambling problems and traumatic brain injury: A population-based study

Traumatic brain injury (TBI) is a common injury characterized by a change in brain function after an external blow to the head and is associated with substance abuse, psychological distress, risk-taking, and impulsivity. Convenience and clinical samples have also linked TBI to problem gambling, but have not ruled out confounding variables such as hazardous drinking and psychological distress. This study examines the relationship between TBI and moderate to severe problem gambling in a general population probability sample controlling for hazardous drinking and psychological distress. The data were obtained from a 2015–2016 cross-sectional general population telephone survey of adults ages 18+from Ontario, Canada (N = 3809). Logistic regression was used to estimate the association as adjusted odds ratios (AOR). Moderate to severe problem gambling was independently associated with a history of TBI after adjusting for potential confounders (AOR: 2.80), and had a statistically significant relationship with psychological distress (AOR = 2.74), hazardous drinking (AOR = 2.69), and lower educational levels (AOR = 0.37). This study provides further data to suggest a link between TBI and moderate to severe problem gambling; however, more research is needed to determine if there is a causal relationship or the potential implications for prevention and treatment

Moderate to severe gambling problems and traumatic brain injury: A population-based study

Traumatic brain injury (TBI) is a common injury characterized by a change in brain function after an external blow to the head and is associated with substance abuse, psychological distress, risk-taking, and impulsivity. Convenience and clinical samples have also linked TBI to problem gambling, but have not ruled out confounding variables such as hazardous drinking and psychological distress. This study examines the relationship between TBI and moderate to severe problem gambling in a general population probability sample controlling for hazardous drinking and psychological distress. The data were obtained from a 2015–2016 cross-sectional general population telephone survey of adults ages 18+from Ontario, Canada (N = 3809). Logistic regression was used to estimate the association as adjusted odds ratios (AOR). Moderate to severe problem gambling was independently associated with a history of TBI after adjusting for potential confounders (AOR: 2.80), and had a statistically significant relationship with psychological distress (AOR = 2.74), hazardous drinking (AOR = 2.69), and lower educational levels (AOR = 0.37). This study provides further data to suggest a link between TBI and moderate to severe problem gambling; however, more research is needed to determine if there is a causal relationship or the potential implications for prevention and treatment

Dopamine D1 receptor stimulation modulates the formation and retrieval of novel object recognition memory: role of the prelimbic cortex

Previous studies have shown that dopamine D1 receptor antagonists impair novel object recognition memory but the effects of dopamine D1 receptor stimulation remain to be determined. This study investigated the effects of the selective dopamine D1 receptor agonist SKF81297 on acquisition and retrieval in the novel object recognition task in male Wistar rats. SKF81297 (0.4 and 0.8mg/kg s.c.) given 15 min before the sampling phase impaired novel object recognition evaluated 10 min or 24h later. The same treatments also reduced novel object recognition memory tested 24h after the sampling phase and when given 15min before the choice session. These data indicate that D1 receptor stimulation modulates both the encoding and retrieval of object recognition memory. Microinfusion of SKF81297 (0.025 or 0.05 μg/side) into the prelimbic sub-region of the medial prefrontal cortex (mPFC) in this case 10 min before the sampling phase also impaired novel object recognition memory, suggesting that the mPFC is one important site mediating the effects of D1 receptor stimulation on visual recognition memory

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Development of cognitive enhancers based on inhibition of insulin-regulated aminopeptidase

The peptides angiotensin IV and LVV-hemorphin 7 were found to enhance memory in a number of memory tasks and reverse the performance deficits in animals with experimentally induced memory loss. These peptides bound specifically to the enzyme insulin-regulated aminopeptidase (IRAP), which is proposed to be the site in the brain that mediates the memory effects of these peptides. However, the mechanism of action is still unknown but may involve inhibition of the aminopeptidase activity of IRAP, since both angiotensin IV and LVV-hemorphin 7 are competitive inhibitors of the enzyme. IRAP also has another functional domain that is thought to regulate the trafficking of the insulin-responsive glucose transporter GLUT4, thereby influencing glucose uptake into cells. Although the exact mechanism by which the peptides enhance memory is yet to be elucidated, IRAP still represents a promising target for the development of a new class of cognitive enhancing agents