Indiana University-Purdue University Indianapolis (IUPUI) / Alcohol-paired cues invigorate alcohol-seeking and drinking behaviors in both rodents and individuals with alcohol use disorder (AUD). Additionally, genetic susceptibility plays a key role in alcohol addiction behaviors. Alcohol preferring (P) rats model both genetic vulnerability and symptoms of AUD. The basolateral amygdala (BLA), prefrontal cortex (PFC), hippocampus (HC) and nucleus accumbens (NA) are important brain regions involved in cued alcohol seeking. These regions are interconnected and their functional connections are hypothesized to be critical in the expression of motivated behaviors. Electrophysiological recordings in these four regions were collected in P rats engaged in a cued alcohol task. Data were filtered in the theta band (5-11 Hz) and segregated by behavioral epoch. The phase locking index γ was computed and used to measure strength of phase locking between signals from any two brain regions. The cross correlation between the amplitude of two signals was used to determine directionality. PFC-NA synchrony increased after stimuli presentation and remained elevated, relative to baseline synchrony. PFC-NA synchrony was also stronger for trials in which the animal made three or more lever presses (rewarded; R), compared to trials in which the animal responded fewer than three times (not-rewarded; NR). During lever pressing, PFC-BLA, NA-HC and PFC-HC synchrony was stronger after presentation of the DS+, in R compared to NR trials. NA-HC and PFC-BLA synchrony was stronger when responses were withheld in extinction, relative to conditioning. These data inform our knowledge of how corticolimbic connections are involved in cued ethanol seeking behaviors.

Synapsins are primarily neuron-specific proteins critical for neurotransmission, synaptogenesis and synapse maintenance. Synapsin II has been specifically linked with increased susceptibility towards developing schizophrenia. Reduced synapsin II mRNA levels were found in the dorsolateral prefrontal cortex (PFC) of patients with schizophrenia. Moreover, synapsin II knockdown in the medial PFC (mPFC) of the adult rat was previously shown to cause schizophrenia-like behaviour and altered expression levels of vesicular proteins involved in glutamatergic and GABAergic signaling within the mPFC. The study of schizophrenia in recent years has shifted to focus on neurodevelopmental players which influence disease outcome. This study was designed to establish the link between neurodevelopmental dysregulation of synapsin II and schizophrenia. Specific knockdown of synapsin II was performed in the mPFC at postnatal day (PD) 7 and PD 17-23. Schizophrenia-like behavioural abnormalities were assessed at pre-pubertal (PD 32-35) and post-pubertal (PD 65-70) stages. Protein estimation of vesicular transporters involved in glutamate, GABA, and dopamine neurotransmitter systems were also assessed in the mPFC. Results from this study indicate (1) synapsin II knockdown during PD 17-23, but not PD 7, caused lasting schizophrenia-like abnormalities (2) abnormalities exhibited permanence at pre-pubertal and post-pubertal stages, and manifested as a function of brain development, (3) behavioural abnormalities were reminiscent of symptoms in established animal models of schizophrenia (i.e. deficits in prepulse inhibition, social withdrawal, locomotor hyperactivity), (4) neurodevelopmental synapsin II alterations induced hypoactive glutamatergic activity through decreased synapsin IIa expression levels (pre-pubertal) and decreased VGLUT-2 expression levels (post-pubertal), and (5) acute olanzapine treatment effectively attenuated schizophrenia-like abnormalities through normalized synapsin IIa expression levels (pre-pubertal) and increased GAD65/67 expression levels (post-pubertal). Results show the causal link between synapsin II expression during critical neurodevelopmental stages and schizophrenia. Additionally, evidence has been provided for the face, construct, and predictive validities of this newly developed animal model of schizophrenia. / Thesis / Doctor of Philosophy (PhD)

The purpose of this systematic review was to characterize further the structural differences in the prefrontal cortex, limbic and paralimbic regions and amygdala alone in psychopaths. Psychopathy is a multifaceted personality disorder characterized by interpersonal and affective traits like lack of empathy, guilt or remorse, shallow affect, and carelessness, as well as behavioral traits such as impulsivity, and poor behavioral control. In recent years, the interest in the neuroanatomical differences in psychopaths has grown. This review aims to understand the prefrontal cortex, limbic and paralimbic areas, and how these regions differ between psychopathic patients and healthy controls. By systematically screening articles that used magnetic resonance imaging (MRI) and voxel based morphometry (VBM) the studies in this review examined people with psychopathic traits. To assess for psychopathy, the most used assessment tool, the Psychopathy Checklist-Revised (PCL-R) was used. Results show that the higher the PCL-R scores of the offenders, the less gray matter volume was found in the superior parts of the prefrontal cortex, limbic and paralimbic areas. Additionally, amygdala deficits in individuals with psychopathy were found. This systematic review may benefit in the way that if we increase our understanding of psychopathy and pave the way forthe creation of effective psychopathic treatments it could prevent future acts of violence. The link between a structural brain anomaly and psychopathy may have a profound clinical, legal, and scientific impact. A psychopathy diagnosis may serve as a precursor to severe societal violence.

<p>Problematic alcohol consumption develops concurrently with deficits in decision-making.  These deficits may be due to alterations in dorsal medial prefrontal cortex (dmPFC) neural activity, as it is essential for the evaluation and implementation of behavioral strategies. In this study, we hypothesized that differences in cognitive control would be evident between Wistars and alcohol-preferring P rats. Cognitive control can be split into proactive and reactive components. Proactive control maintains goal-directed behavior independent of a stimulus whereas reactive control elicits goal-directed behavior at the time of a stimulus. Specifically, it was hypothesized that Wistars would show proactive control over alcohol-seeking whereas P rats </p> <p>would show reactive control over alcohol-seeking. Proactive control in our rodent model is defined as responding to distal task cues whereas reactive control is responding to proximal cues. This was tested in rodents performing a 2-way Cued Access Protocol (2CAP) that facilitates measurements of alcohol seeking and drinking. Congruent sessions were the typical, default 2CAP sessions that consisted of the CS+ being on the same side as alcohol access. These were compared with incongruent sessions where alcohol access was opposite of the CS+. Wistars exhibited an increase in incorrect approaches during the incongruent sessions, which was not detectable in P rats. A trial-by-trial analysis indicated that the increases in incorrect responses </p> <p>was explained by Wistars utilizing the previously learned task-rule, whereas the P rats did not. </p> <p>This motivated the subsequent hypothesis that neural activity patterns corresponding to proactive control would be observable in Wistars but not P rats. Principal Component Analysis indicated that neural ensembles in the dmPFC of Wistars exhibited decreased activity to the cue light in incongruent sessions whereas P rat ensembles displayed increased activity at timepoints associated with the onset and end of alcohol access. Overall, it was observed that P rats showed the most differences in neural activity at times relevant for alcohol delivery; specifically, when the sipper came into the apparatus and left. Conversely, Wistars showed differences prior to approach as evidenced by both differences in cue-related activity as well as differences in </p> <p>spatial-strategies. Together, these results support our hypothesis that Wistars are more likely to engage proactive cognitive control strategies whereas P rats are more likely to engage reactive cognitive control strategies. Although P rats were bred to prefer alcohol, differences in cognitive control phenotypes may have concomitantly occurred that are of clinical relevance.</p>

Neuroscience research has been largely focused on neurons, while an equally important cell type, glia, was sidelined until recently. Astrocytes are star-shaped glial cells responsible for a variety of homeostatic processes of the central nervous system in addition to participating in synaptogenesis and neuronal signal transmission. A variety of immunohistochemical markers have been utilized to visualize these cells in the brain including glial fibrillary acidic protein (GFAP), vimentin, and aldehyde dehydrogenase 1 family member L1 (ALDH1L1). The current study makes use of a multiplex immunohistochemistry protocol developed in collaboration with General Electric to stain rhesus monkey brain tissue samples from the lateral prefrontal cortex (LPFC; n=5) and the primary visual cortex (V1; n=4) with a large number of markers, including GFAP, vimentin, and ALDH1L1 as well as neuronal, microglial, and oxidative stress markers. Using algorithms and manual cell classification, we were able to obtain neuronal and astrocytic counts and use these to estimate astrocyte-to-neuron ratios (ANRs) of the individual brain areas and laminae as well as assess the relative intensity of the markers of interest between areas. Among our findings there was higher ANRs in LPFC compared to V1 gray matter as well as in layer 1 compared to layer 2 in both areas studied. There is also a higher density of astrocytes in layer 1 potentially due to the recognized lack of neurons in this layer. We found significantly higher intensities of GFAP across all gray matter layers in V1 compared to LPFC as well as higher intensities for TSPO and Cleaved Caspase-3 in some V1 layers compared to their LPFC counterparts. This higher intensity of V1 reactive astrocyte markers are potentially due to the increased number of neurons these astrocytes need to support as demonstrated by the low ANR seen in V1 when compared to LPFC. In order to further our knowledge of normal astrocyte properties in these brain areas, it is imperative that we confirm our counts with stereologic studies and include oligodendrocyte markers in our multiplex staining protocol in order to better assess glial numbers within our sections. Additionally, morphological studies assessing rhesus monkey astrocytes identified with a variety of markers is important as we have shown that no one marker stains all astrocytes even though most astrocytes express more than one marker at a time.

No description available.

Rhythmic oscillations in neuronal activity display variations in amplitude (power) over a range of frequencies. Attention and cognitive performance correlate with increases in cortical gamma oscillations (40-70Hz) that are generated by the coordinated firing of glutamatergic pyramidal neurons and GABAergic interneurons, and are modulated by dopamine. In the medial prefrontal cortex (mPFC) of rats, gamma power increases during treadmill walking, or after administration of an acute subanesthetic dose of the NMDA receptor antagonist ketamine. Ketamine is also used to mimic symptoms of schizophrenia, including cognitive deficits, in healthy humans and rodents. Additionally, the ability of a drug to modify ketamine-induced gamma power has been proposed to predict its pro-cognitive therapeutic efficacy. However, the mechanism underlying ketamine-induced gamma oscillations is poorly understood. We hypothesized that gamma oscillations induced by walking and ketamine would be generated by a shared mechanism in the mPFC and one of its major sources of innervation, the mediodorsal thalamus (MD). Recordings from chronically implanted electrodes in rats showed that both treadmill walking and ketamine increased gamma power, firing rates, and spike-gamma LFP correlations in the mPFC. By contrast, in the MD, treadmill walking increased all three measures, but ketamine decreased firing rates and spike-gamma LFP correlations while increasing gamma power. Therefore, walking- and ketamine-induced gamma oscillations may arise from a shared circuit in the mPFC, but different circuits in the MD. Recent work in normal animals suggests that dopamine D4 receptors (D4Rs) synergize with the neuregulin/ErbB4 signaling pathway to modulate gamma oscillations and cognitive performance. Consequently, we hypothesized that drugs targeting the D4Rs and ErbB receptors would show pro-cognitive potential by reducing ketamine-induced gamma oscillations in mPFC. However, when injected before ketamine, neither the D4R agonist nor antagonist altered ketamine’s effects on gamma power or firing rates in the mPFC, but the pan-ErbB antagonist potentiated ketamine’s increase in gamma power, and prevented ketamine from increasing firing rates. This indicates that D4Rs and ErbB receptors influence gamma power via distinct mechanisms that interact with NMDA receptor antagonism differently. Our results highlight the value of using ketamine-induced changes in gamma power as a means of testing novel pharmaceutical agents.

yes / Rationale: Dopamine dysregulation in the prefrontal cortex (PFC) plays an important role in cognitive dysfunction in schizophrenia. Sub-chronic phencyclidine (scPCP) treatment produces cognitive impairments in rodents and is a thoroughly validated animal model for cognitive deficits in schizophrenia. The aim of our study was to investigate the role of PFC dopamine in scPCP-induced deficits in a cognitive task of relevance to the disorder, novel object recognition (NOR). Methods: Twelve adult female Lister Hooded rats received scPCP (2 mg/kg) or vehicle via the intraperitoneal route twice daily for seven days, followed by seven days washout. In vivo microdialysis was carried out prior to, during and following the NOR task. Results: Vehicle rats successfully discriminated between novel and familiar objects and this was accompanied by a significant increase in dopamine in the PFC during the retention trial (P<0.01). scPCP produced a significant deficit in NOR (P<0.05 vs. control) and no PFC dopamine increase was observed. Conclusions: These data demonstrate an increase in dopamine during the retention trial in vehicle rats that was not observed in scPCP-treated rats accompanied by cognitive disruption in the scPCP group. This novel finding suggests a mechanism by which cognitive deficits are produced in this animal model and support its use for investigating disorders in which PFC dopamine is central to the pathophysiology.

Yes / The difference between Apolipoprotein E ε4 carriers and non-carriers in response to single exercise sessions was tested. Stroop and Posner tasks were administered to young untrained women immediately after walking sessions or moderately heavy exercise. Exercise had a significantly more profound impact on the Stroop effect than on the Posner effect, suggesting selective involvement of prefrontal function. A significant genotype-by-exercise interaction indicated differences in response to exercise between ε4 carriers and non-carriers. Carriers showed facilitation triggered by exercise. The transient executive down-regulation was construed as due to exercise-dependent hypofrontality. The facilitation observed in carriers was interpreted as better management of prefrontal metabolic resources, and explained within the antagonistic pleiotropy hypothesis framework. The findings have implications for the interpretation of differences between ε4 carriers and non-carriers in the benefits triggered by long-term exercise that might depend, at least partially, on mechanisms of metabolic response to physical activity. / Partially supported by a University of Hull Faculty of Science scholarship to MDM and by funding from MIUR and FP7 VPH-DARE to AV.

No description available.