Differential release of dopamine in the nucleus accumbens evoked by low-versus high-frequency medial prefrontal cortex stimulation

The medial prefrontal cortex (mPFC) coordinates goal-directed behaviors, which may be mediated through mPFC regulation of dopamine release in the nucleus accumbens (NAc). Furthermore, frequency-specific oscillatory activity between the frontal cortex and downstream structures may facilitate inter-region communication. Although high-frequency (e.g., 60 Hz) mPFC stimulation is known to increase basal dopamine levels in the NAc, little is known about how phasic dopamine release is affected by mPFC stimulation. Understanding the frequency-specific control of phasic dopamine release by mPFC stimulation could elucidate mechanisms by which the mPFC modulates other regions. It could also inform optimization of deep brain stimulation for treatment of neurological disorders.

Intrinsic connectivity between the hippocampus,nucleus accumbens,and ventral tegmental area in humans

Recent studies suggest that memory formation in the hippocampus is modulated by the motivational significance of events, allowing past experience to adaptively guide behavior. The effects of motivation on memory are thought to depend on interactions between the hippocampus, the ventral tegmental area (VTA), and the nucleus accumbens (NAcc). Indeed, animal studies reveal anatomical pathways for circuit‐level interaction between these regions. However, a homologue circuit connectivity in humans remains to be shown. We characterized this circuitry in humans by exploiting spontaneous low‐frequency modulations in the fMRI signal (termed resting‐state functional connectivity), which are thought to reflect functionally related regions and their organization into functional networks in the brain. We examined connectivity in this network across two datasets (hi‐resolution, n = 100; standard resolution, n = 894). Results reveal convergent connectivity between the hippocampus, and both the NAcc and the VTA centered on ventral regions in the body of the hippocampus. Additionally, we found individual differences in the strength of connectivity within this network. Together, these results provide a novel task‐independent characterization of circuitry underlying interactions between the hippocampus, NAcc, and VTA and provide a framework with which to understand how connectivity might reflect and constrain the effects of motivation on memory. © 2012 Wiley Periodicals, Inc.     

Adaptations in reward-related behaviors and mesolimbic dopamine function during motherhood and the postpartum period

Initiation and maintenance of maternal behavior is driven by a complex interaction between the physiology of parturition and offspring stimulation, causing functional changes in maternal brain and behavior. Maternal behaviors are among the most robust and rewarding motivated behaviors. Mesolimbic dopamine (DA) system alterations during pregnancy and the postpartum enable enhanced reward-related responses to offspring stimuli. Here, we review behavioral evidence demonstrating postpartum rodents exhibit a bias towards pups and pup-related stimuli in reward-related tasks. Next, we provide an overview of normative adaptations in the mesolimbic DA system induced by parturition and the postpartum, which likely mediate shifts in offspring valence. We also discuss a causal link between dopaminergic dysfunction and disrupted maternal behaviors, which are recapitulated in postpartum depression (PPD) and relevant rodent models. In sum, mesolimbic DA system activation drives infant-seeking behavior and strengthens the mother-infant bond, potentially representing a therapeutic target for reward-related deficits in PPD.     

TrkB inhibition as a therapeutic target for CNS-related disorders

The interaction of brain-derived neurotrophic factor (BDNF) with its tropomyosin-related kinase receptor B (TrkB) is involved in fundamental cellular processes including neuronal proliferation, differentiation and survival as well as neurotransmitter release and synaptic plasticity. TrkB signaling has been widely associated with beneficial, trophic effects and many commonly used psychotropic drugs aim to increase BDNF levels in the brain. However, it is likely that a prolonged increased TrkB activation is observed in many pathological conditions, which may underlie the development and course of clinical symptoms. Interestingly, genetic and pharmacological studies aiming at decreasing TrkB activation in rodent models mimicking human pathology have demonstrated a promising therapeutic landscape for TrkB inhibitors in the treatment of various diseases, e.g. central nervous system (CNS) disorders and several types of cancer. Up to date, only a few selective and potent TrkB inhibitors have been developed. As such, the use of crystallography and in silico approaches to model BDNF-TrkB interaction and to generate relevant pharmacophores represent powerful tools to develop novel compounds targeting the TrkB receptor.     

Systemic administration of d-penicillamine prevents the locomotor activation after intra-VTA ethanol administration in rats

Although recently published studies seem to confirm the important role displayed by acetaldehyde (ACH), the main metabolite of ethanol, in the behavioral effects of ethanol, the origin of ACH is still a matter of debate. While some authors confer more importance to the central (brain metabolism) origin of ACH, others indicate that the hepatic origin could be more relevant. In this study we have addressed this topic using an experimental approach that combines local microinjections of ethanol into the ventral tegmental area (VTA) (which guarantees the brain origin of the ACH) to induce motor activation in rats together with systemic administration (i.p.) of several doses (0, 12.5, 25 and 50 mg/kg) of d-penicillamine (DP), a sequestering agent of ACH with contrasted efficiency to abolish the behavioral effects of the drug. Our results clearly show that DP prevented in a dose-dependent manner the motor activation induced by intra-VTA ethanol, being the 50 mg/kg dose the most efficient. DP per se did not affect the basal activity of the rats. In order to determine the specificity of the DP action, we also studied the effects of DP 50 mg/kg on the DAMGO-induced motor activation after the intra-VTA administration of this μ-opioid receptors agonist. DP did not significantly modify the motor activation induced by DAMGO thus confirming the specificity of the DP effects. Our results clearly suggest that the brain-derived ACH is necessary to manifest the activating effects resulting from ethanol administration.     

Epidemiology-driven neurodevelopmental animal models of schizophrenia

Human epidemiological studies have provided compelling evidence that the risk of developing schizophrenia is significantly enhanced following prenatal and/or perinatal exposure to various environmental insults, including maternal exposure to stress, infection and/or immune activation, nutritional deficiencies and obstetric complications. Based on these associations, a great deal of interest has been centered upon the establishment of neurodevelopmental animal models which are based on prenatal and/or perinatal exposure to such environmental stimuli. In the present review, we describe this relatively novel class of epidemiology-based animal models in relation to the etiology, neurobiology and psychopharmacology of schizophrenia. Thereby, we discuss the general design and practical implementation of these models, and we provide an integrative summary of experimental findings derived from diverse epidemiology-based models, including models of maternal exposure to psychological stress, glucocorticoid treatment, viral infection, immune activating agents, protein deprivation, vitamin D deficiency, as well as models of obstetric complications in the form of birth by Caesarian section and perinatal/postnatal hypoxia. We highlight that the long-term consequences of prenatal exposure to these environmental challenges in animals successfully capture a broad spectrum of structural and functional brain abnormalities implicated in schizophrenia, some of which can be normalized by acute and/or chronic antipsychotic drug treatment. We thus conclude that epidemiology-driven neurodevelopmental models of schizophrenia are characterized by a high level of face, construct and predictive validity, including intrinsic etiological significance to the disorder. They also fulfill the expectation of the neurodevelopmental theory, such that the effects of prenatal environmental insults often only emerge after puberty. Epidemiologically based animal models not only provide indispensable experimental tools to test the hypothesis of causality in human epidemiological associations, but they also offer important new avenues for the elucidation of neurobiological, neuroendocrine and neuroimmunological mechanisms involved in the etiopathogenesis of schizophrenia and related disorders.     

Neurodegenerative disorders share common features of “loss of function” states of a proposed mechanism of nervous system functions

Neurodegenerative disorders are highly heterogeneous for the locations affected and the nature of the aggregated proteins. Nearly 80% of the neurodegenerative disorders occur sporadically, indicating that certain factors must combine to initiate the degenerative changes. The contiguous extension of degenerative changes from cell to cell, the association with viral fusion proteins, loss of dendritic spines (postsynaptic terminals), and the eventual degeneration of cells indicate the presence of a unique mechanism for inter-cellular spread of pathology. It is not known whether the “loss of function” states of the still unknown normal nervous system operations can lead to neurodegenerative disorders. Here, the possible loss of function states of a proposed normal nervous system function are examined. A reversible inter-postsynaptic functional LINK (IPL) mechanism, consisting of transient inter-postsynaptic membrane (IPM) hydration exclusion and partial to complete IPM hemifusions, was proposed as a critical step necessary for the binding process and the induction of internal sensations of higher brain functions. When various findings from different neurodegenerative disorders are systematically organized and examined, disease features match the effects of loss of function states of different IPLs. Changes in membrane composition, enlargement of dendritic spines by dopamine and viral fusion proteins are capable of altering the IPLs to form IPM fusion. The latter can lead to the observed lateral spread of pathology, inter-neuronal cytoplasmic content mixing and abnormal protein aggregation. Since both the normal mechanism of reversible IPM hydration exclusion and the pathological process of transient IPM fusion can evade detection, testing their occurrence may provide preventive and therapeutic opportunities for these disorders.     

Ventral tegmental self-stimulation selectively induces opioid peptide release in rat CNS

Intracranial self-stimulation (ICS) is thought to activate neuronal systems involved in processing natural reinforcing agents. Metabolic mapping studies have previously demonstrated a subset of CNS structures specifically engaged by ICS in animals receiving stimulation actively vs. passively. Since opiates are known to enhance JCS behavior and presumably its reinforcing properties, the current study addressed the question of the role of opioid peptides as mediators of ICS. Rats were trained on a fixed ration (FR) 20 schedule of responding maintained by ICS. Following response stabilization, rats were assigned either to an active or a corresponding yoked stimulation group at 1 of 2 schedules of reinforcement (i. e., FR1-YFR1, FR20-YFR20, or sedentary control), and opioid peptide release was inferred from in vivo receptor occupancy. Autoradiographic analyses identified 3 groups of structures. Treatment-induced alterations in occupancy were seen in the medial dorsal nucleus of the thalamus, basolateral amygdala, ventral pallidum, medial habenula, dorsal raphe, posterior hypothalamus, substantia nigra pars compacta, agranular preinsular cortex, and zona incerta. Depending upon the structure, peptide release was dependent upon stimulus contingency (active vs. yoked) and/or schedule (FR1 vs. FR20). Evidence for ICS-induced inhibition of peptide release was found in the habenula and preinsular cortex. Nine additional structures, all components of, or receiving projections from, the limbic system, revealed complex interactions between ICS treatment and the electrode side. Finally, a widespread ipsilateral increase in receptor binding was seen rostrally from the cingulate, olfactory tubercle, and nucleus accumbens, along the lateral hypothalamus and hippocampus, and extending caudally to the substantia nigra and ventral tegmentum. These later effects appear to be related to stimulation-induced changes in blood flow and subsequent ligant presentation increases. Collectively, these data point towards the ability of rewarding brain stimulation to activate discrete neuronal opioid systems contingent upon specific behavioral as well as stimulus conditions. © 1993 Wiley-Liss, Inc.     

Electrophysiological evidence for an input from the anterior olfactory nucleus to substantia nigra.

Extracellular recordings were made from spontaneously active neurons in the substantia nigra (SN) region of halothane-anesthetized rats. Histologically identified neurons recorded in the dopamine (DA)-rich zona compacta (ZC) region could be distinguished from those in the zona reticulata (ZR) region on the basis of action potential duration, firing frequency, and responsiveness to intravenously administered DA agonist and antagonist drugs. Electrical stimulation of the ipsilateral anterior olfactory nucleus evoked complex excitatory and inhibitory responses in the majority (69%) of the ZC cells studied; but only in 2 of 30 cells from the ZR. Electrical stimuli delivered to the limbs were effective in influencing the firing rate of only a few cells. These results indicate that a connection exists, possibly via the medial forebrain bundle, between olfactory systems and the DA-containing cells of the SN.