Rodent models of human alcoholism: implications for a role of neuropeptide Y and corticotropin releasing factor

Rodent models of alcoholism have been integral in discovering candidate genes and neurochemicals involved in this disease. Two promising candidates include neuropeptide Y (NPY) and corticotropin releasing factor (CRF). It has been hypothesized that NPY and CRF exert a reciprocal regulation of ethanol self-administration through allosteric interactions within the extended amygdala. Therefore, the goal of the present report was to determine if NPY and CRF modulate ethanol relapse- and binge-like drinking behaviors through the use of recently developed rodent models. Experiment 1 utilized the NPY -/- mouse to determine if NPY modulates withdrawal-induced anxiety, a component of ethanol relapse. Compared to the NPY +/+ mice, NPY -/- mice exhibited increased withdrawal-induced anxiety as measured by the elevated plus maze (EPM) test. Although, we did not examine CRF, previous research has revealed that a hyperactive CRF system contributes to withdrawal-induced anxiety. Experiment 2 expanded on previous findings by examining the role of NPY and CRF on excessive ethanol relapse-like consumption, as measured by the alcohol deprivation effect (ADE). We found that female NPY -/- mice exhibited increased post-deprivation ethanol drinking (i.e., the ADE) that endured for several deprivation cycles. Interestingly, the male NPY -/- mice did not exhibit the ADE during any deprivation cycle. Additionally, we found that acute administration of CP-154,526, a highly selective CRF1 receptor antagonist, reduced the expression of the ADE in mice. Experiment 3 examined the role of CRF on excessive or binge-like drinking as modeled by drinking in the dark (DID) procedures. We found that administration of CP-154,526 reduced excessive, but not moderate, ethanol drinking suggesting a possible role for CRF in binge drinking. Taken together, these experiments provide evidence for a role of both NPY and CRF in the modulation of multiple behaviors and neurobiological responses that may underlie alcohol abuse disorders and alcoholism. Ultimately, pharmacological compounds that target these systems may be of potential therapeutic value for the treatment of alcoholism

Big Bang nucleosynthesis revisited via Trojan Horse Method measurements

Nuclear reaction rates are among the most important input for understanding the primordial nucleosynthesis and therefore for a quantitative description of the early Universe. An up-to-date compilation of direct cross sections of 2H(d,p)3H, 2H(d,n)3He, 7Li(p,alpha)4He and 3He(d,p)4He reactions is given. These are among the most uncertain cross sections used and input for Big Bang nucleosynthesis calculations. Their measurements through the Trojan Horse Method (THM) are also reviewed and compared with direct data. The reaction rates and the corresponding recommended errors in this work were used as input for primordial nucleosynthesis calculations to evaluate their impact on the 2H, 3,4He and 7Li primordial abundances, which are then compared with observations.Comment: 22 pages, 7 figures, accepted for publication in The Astrophysical Journa

A GABAergic projection from the centromedial nuclei of the amygdala to ventromedial prefrontal cortex modulates reward behavior

The neural circuitry underlying mammalian reward behaviors involves several distinct nuclei throughout the brain. It is widely accepted that the midbrain dopamine (DA) neurons are critical for the reward-related behaviors. Recent studies have shown that the centromedial nucleus of the amygdala (CeMA) has a distinct role in regulating reward-related behaviors. However, the CeMA and ventromedial PFC (vmPFC) interaction in reward regulation remains poorly understood. Here, we identify and dissect a GABAergic projection that originates in the CeMA and terminates in the vmPFC (VGat-Cre(CeMA-vmPFC)) using viral-vector-mediated, cell-type-specific optogenetic techniques in mice. Pathway-specific optogenetic activation of the VGat-Cre(CeMA-vmPFC) circuit in awake, behaving animals produced a positive, reward-like phenotype in real-time place preference and increased locomotor activity in open-field testing. In sucrose operant conditioning, the photoactivation of these terminals increased nose-poking effort with no effect on licking behavior and robustly facilitated the extinction of operant behavior. However, photoactivation of these terminals did not induce self-stimulation in the absence of an external reward. The results described here suggest that the VGat-Cre(CeMA-vmPFC) projection acts to modulate existing reward-related behaviors. SIGNIFICANCE STATEMENT Many studies have shown that the interactions between the centromedial nucleus of the amygdala (CeMA) and ventromedial PFC (vmPFC) have critical roles for emotional regulation. However, most studies have associated this circuit with fear and anxiety behaviors and emphasized top-down processing from vmPFC to CeMA. Here, we provide new evidence for bottom-up CeMA to vmPFC influence on reward-related behaviors. Although previous work implicated the CeMA in incentive salience, our results isolate the investigation to a specific CeMA GABAergic projection to the vmPFC. This long-range GABAergic interaction between amygdala and frontal cortex adds a new dimension to the complex regulation of reward-related behaviors

8B reaction dynamics researched at HIE-ISOLDE

For the first time a measurement of 8B + 64Zn reaction has been performed at HIE-ISOLDE at CERN at energies around the Coulomb barrier, to understand how the debated halo structure of the light nucleus can affect reaction dynamics

Elevated anxiety-like behavior following ethanol exposure in mutant mice lacking neuropeptide Y (NPY)

Neuropeptide Y (NPY) is a neuromodulator with anxiolytic properties. Recent evidence suggests that NPY modulates neurobiological responses to ethanol. Because withdrawal from ethanol is associated with elevated anxiety-like behavior, and because central NPY modulates anxiety, we assessed anxiety-like behavior in mutant mice lacking normal production of NPY (NPY−/−) and in normal wild-type mice (NPY+/+) 6-hours after removal of a liquid diet containing 4.5% ethanol

Optogenetic strategies to investigate neural circuitry engaged by stress

Optogenetic techniques have given researchers unprecedented access to the function of discrete neural circuit elements and have been instrumental in the identification of novel brain pathways that become dysregulated in neuropsychiatric diseases. For example, stress is integrally linked to the manifestation and pathophysiology of neuropsychiatric illness, including anxiety, addiction and depression. Due to the heterogeneous populations of genetically and neurochemically distinct neurons in areas such as the bed nucleus of the stria terminalis (BNST), as well as their substantial number of projections, our understanding of how neural circuits become disturbed after stress has been limited. Using optogenetic tools, we are now able to selectively isolate distinct neural circuits that contribute to these disorders and perturb these circuits in vivo, which in turn may lead to the normalization of maladaptive behavior. This review will focus on current optogenetic strategies to identify, manipulate, and record from discrete neural circuit elements in vivo as well as highlight recent optogenetic studies that have been utilized to parcel out BNST function

Effects of Food Availability and Administration of Orexigenic and Anorectic Agents on Elevated Ethanol Drinking Associated With Drinking in the Dark Procedures

Drinking in the dark (DID) procedures have recently been developed to induce high levels of ethanol drinking in C57BL/6J mice, which result in blood ethanol concentrations reaching levels that have measurable affects on physiology and/or behavior. The present study determined if increased ethanol drinking associated with DID procedures may be motivated by caloric need rather than by the post-ingestive pharmacological effects of ethanol. To this end, food availability was manipulated or mice were given peripheral administration of orexigenic or anorectic agents during DID procedures

Involvement of protein kinase A in ethanol-induced locomotor activity and sensitization

Mutant mice lacking the RIIβ subunit of protein kinase A (regulatory subunit II beta−/−) show increased ethanol preference. Recent evidence suggests a relationship between heightened ethanol preference and susceptibility to ethanol-induced locomotor sensitization. It is currently unknown if protein kinase A signaling modulates the stimulant effects and/or behavioral sensitization caused by ethanol administration. To address this question, we examined the effects of repeated ethanol administration on locomotor activity RIIβ−/− and littermate wild-type (RIIβ+/+) mice on multiple genetic backgrounds

Predictors of High Ethanol Consumption in RII?? Knock-Out Mice: Assessment of Anxiety and Ethanol-Induced Sedation

Genetic and pharmacological evidence suggests that the cyclic adenosine monophosphate–dependent protein kinase A pathway modulates neurobiological responses to ethanol. Mutant mice lacking the RIIβ subunit of protein kinase A (RIIβ) are resistant to ethanol-induced sedation and drink significantly more ethanol than littermate wild-type mice (RIIβ). We determined whether high ethanol intake by the RIIβ mice on alternate genetic backgrounds is reliably predicted by high basal levels of anxiety or resistance to the sedative effects of ethanol. Two-bottle choice procedures and a battery of behavioral tests (elevated plus maze, open-field activity, and zero maze) were used to assess voluntary ethanol consumption and basal levels of anxiety in RIIβ and RIIβ mice on either a C57BL/6J or a 129/SvEv × C57BL/6J genetic background. Additionally, ethanol-induced sedation and blood ethanol levels were determined in RIIβ and RIIβ mice after intraperitoneal injection of ethanol (3.8 g/kg). RIIβ mice on both genetic backgrounds consumed more ethanol and had a greater preference for ethanol relative to RIIβ mice. However, RIIβ mice showed reduced basal levels of anxiety when maintained on the C57BL/6J background but showed increased anxiety when maintained on the 129/SvEv × C57BL/6J background. Consistent with prior research, RIIβ mice were resistant to the sedative effects of ethanol, regardless of the genetic background. Finally, RIIβ and RIIβ mice showed similar blood ethanol levels. These results indicate that high ethanol consumption is associated with resistance to the sedative effects of ethanol but that basal levels of anxiety, as well as ethanol metabolism, do not reliably predict high ethanol drinking by RIIβ mice

Increased Consumption but Not Operant Self-administration of Ethanol in Mice Lacking the RIIbeta Subunit of Protein Kinase A

Accumulating evidence indicates that cAMP-dependent protein kinase A (PKA) is involved in the neurobiological responses to ethanol. Previous reports indicate that mice lacking the RIIβ subunit of PKA (RIIβ−/−) voluntarily consume more ethanol than wild-type controls (RIIβ+/+) using two-bottle testing procedures. While such procedures primarily measure consummatory behavior, operant self-administration procedures allow analysis of consummatory as well as appetitive or “ethanol-seeking” behavior (i.e., lever pressing is required to gain access to the ethanol solution). Therefore, we determined if the high ethanol consumption characteristic of RIIβ−/− mice would be complimented by increased appetitive ethanol-seeking behavior in an operant paradigm