Altered neural oscillations and elevated dopamine levels in the reward pathway during alcohol relapse.

Alcohol use disorder (AUD) is a severe chronic condition characterized by compulsive alcohol use, cravings and high relapse rates even after long periods of abstinence. It is suggested that alterations in neuronal network activity, especially in the reward pathway accompany or even mediate relapse behavior. Here we used a DSM-based rat model to map in a first set of experiments neurochemical alterations in the reward pathway during alcohol relapse. Compared to the abstinence condition, we found specific elevation of dopamine levels in the nucleus accumbens shell and the medial prefrontal cortex. We then conducted local field potential (LFP) recordings in these brain sites and observed decreased low-beta oscillatory activity in the nucleus accumbens shell and increased high beta activity in the medial prefrontal cortex. In conclusion, as in comparison with abstinence from alcohol, alcohol relapse is associated with enhanced dopamine levels in the mesolimbic system and an inverse correlation between ß oscillatory activity and dopamine availability in the nucleus accumbens shell. These findings suggest that during a relapse situation reduced synchronous oscillatory activity of the local neural population in the nucleus accumbens shell occurs. This local neural population presumably relates to dopaminoceptive medium spiny neurons that show reduced synchronicity during a relapse situation.

Deep brain stimulation during early adolescence prevents microglial alterations in a model of maternal immune activation.

In recent years schizophrenia has been recognized as a neurodevelopmental disorder likely involving a perinatal insult progressively affecting brain development. The poly I:C maternal immune activation (MIA) rodent model is considered as a neurodevelopmental model of schizophrenia. Using this model we and others demonstrated the association between neuroinflammation in the form of altered microglia and a schizophrenia-like endophenotype. Therapeutic intervention using the anti-inflammatory drug minocycline affected altered microglia activation and was successful in the adult offspring. However, less is known about the effect of preventive therapeutic strategies on microglia properties. Previously we found that deep brain stimulation of the medial prefrontal cortex applied pre-symptomatically to adolescence MIA rats prevented the manifestation of behavioral and structural deficits in adult rats. We here studied the effects of deep brain stimulation during adolescence on microglia properties in adulthood. We found that in the hippocampus and nucleus accumbens, but not in the medial prefrontal cortex, microglial density and soma size were increased in MIA rats. Pro-inflammatory cytokine mRNA was unchanged in all brain areas before and after implantation and stimulation. Stimulation of either the medial prefrontal cortex or the nucleus accumbens normalized microglia density and soma size in main projection areas including the hippocampus and in the area around the electrode implantation. We conclude that in parallel to an alleviation of the symptoms in the rat MIA model, deep brain stimulation has the potential to prevent the neuroinflammatory component in this disease.

Rats overexpressing the dopamine transporter display behavioral and neurobiological abnormalities with relevance to repetitive disorders.

The dopamine transporter (DAT) plays a pivotal role in maintaining optimal dopamine signaling. DAT-overactivity has been linked to various neuropsychiatric disorders yet so far the direct pathological consequences of it has not been fully assessed. We here generated a transgenic rat model that via pronuclear microinjection overexpresses the DAT gene. Our results demonstrate that DAT-overexpression induces multiple neurobiological effects that exceeded the expected alterations in the corticostriatal dopamine system. Furthermore, transgenic rats specifically exhibited behavioral and pharmaco-therapeutic profiles phenotypic of repetitive disorders. Together our findings suggest that the DAT rat model will constitute a valuable tool for further investigations into the pathological influence of DAT overexpression on neural systems relevant to neuropsychiatric disorders.

Testing different paradigms to optimize antidepressant deep brain stimulation in different rat models of depression.

Deep brain stimulation (DBS) of several targets induces beneficial responses in approximately 60% of patients suffering from treatment-resistant depression (TRD). The remaining 40% indicate that these stimulation sites do not bear therapeutic relevance for all TRD patients and consequently DBS-targets should be selected according to individual symptom profiles. We here used two animal models of depression known to have different genetic backgrounds and behavioral responses: the therapy-responsive Flinders sensitive line (FSL) and the therapy-refractory congenitally learned helpless rats (cLH) to study symptom-specific DBS effects i) of different brain sites ii) at different stimulation parameters, and iii) at different expressions of the disease. Sham-stimulation/DBS was applied chronic-intermittently or chronic-continuously to either the ventromedial prefrontal cortex (vmPFC, rodent equivalent to subgenual cingulate), nucleus accumbens (Nacc) or subthalamic nucleus (STN), and effects were studied on different depression-associated behaviors, i.e. anhedonia, immobility/behavioral despair and learned helplessness. Biochemical substrates of behaviorally effective versus ineffective DBS were analyzed using in-vivo microdialysis and post-mortem high-performance liquid chromatography (HPLC). We found that i) vmPFC-DBS outperforms Nacc-DBS, ii) STN-DBS increases depressive states, iii) chronic-continuous DBS does not add benefits compared to chronic-intermittent DBS, iv) DBS-efficacy depends on the disease expression modeled and iv) antidepressant DBS is associated with an increase in serotonin turnover alongside site-specific reductions in serotonin contents. The reported limited effectiveness of vmPFC DBS suggests that future research may consider the specific disease expression, investigation of different DBS-targets and alternative parameter settings.

Acute high frequency stimulation of the prefrontal cortex or nucleus accumbens does not increase hippocampal neurogenesis in rats.

To date, the effects of deep brain stimulation (DBS) on hippocampal neurogenesis have been mainly characterized in the context of memory. Acute stimulation (i.e. for 1 h) of either the entorhinal cortex or the anterior thalamus increases both cell proliferation and survival. We investigate whether stimulation applied to targets being considered for the treatment of depression, namely the ventromedial prefrontal cortex (vmPFC) or nucleus accumbens (Acb), also increases hippocampal neurogenesis in rodents. Rats were treated with vmPFC or Acb DBS for 1 h at different settings. 5'-bromo-2'deoxyuridine (BrdU) was injected three days following stimulation onset and animals were sacrificed 24 h or 28 days later. Overall, we found that neither vmPFC nor Acb DBS increased hippocampal neurogenesis. In summary, the delivery of acute stimulation into targets homologous to those used in human depression trials does not increase hippocampal neurogenesis.

Altered local field potential activity and serotonergic neurotransmission are further characteristics of the Flinders sensitive line rat model of depression.

A significant portion of patients suffering from major depression remains refractory to available antidepressant treatment strategies. This highlights the need for a better understanding of the underlying neuropathology in order to develop rationale-based treatments. Here we aimed to further characterize neurobiological abnormalities of the Flinders Sensitive Line (FSL) rat model of depression. Biochemically, in FSL rats we mainly found increased levels of serotonin in most cortical and subcortical brain regions when compared to controls. Using electrophysiological measurements, in FSL rats we found decreased alpha, beta and low gamma oscillatory activity in the medial prefrontal cortex and nucleus accumbens and decreased alpha and beta as well as increased low gamma oscillatory activity in the subthalamicus nucleus when compared to controls. In summary, we show distinct neurochemical properties in combination with particular oscillatory activity patterns for brain areas thought to be pathophysiologically relevant for depression. Our data contribute to the further understanding of neurobiological alterations in the FSL rat model of depression that could provide a basis for research into future therapeutic strategies.

Medial Forebrain Bundle Deep Brain Stimulation has Symptom-specific Anti-depressant Effects in Rats and as Opposed to Ventromedial Prefrontal Cortex Stimulation Interacts With the Reward System.

BACKGROUND: In recent years, deep brain stimulation (DBS) has emerged as a promising treatment option for patients suffering from treatment-resistant depression (TRD). Several stimulation targets have successfully been tested in clinical settings, including the subgenual cingulum (Cg25) and the medial forebrain bundle (MFB). MFB-DBS has led to remarkable results, surpassing the effect of previous targets in terms of response latency and number of responders. However, the question remains as to which mechanisms underlie this difference. OBJECTIVE/HYPOTHESIS: The aim of the present study was to thoroughly study the anti-depressant effect of MFB-DBS in the Flinders sensitive line (FSL) rat model of depression as well as to investigate whether MFB-DBS and Cg25-DBS operate through the same neurobiological circuits. METHODS: FSL and control rats received bilateral high-frequency stimulation to the MFB at the level of the lateral hypothalamus, while being subjected to a variety of depression- and anxiety-related behavioral paradigms. To further compare the effects of MFB-DBS and Cg25-DBS on reward-related behavior, animals were stimulated in either the MFB or ventromedial prefrontal cortex (vmPFC, rodent analog to Cg25), while being tested in the intra-cranial self-stimulation paradigm. RESULTS: A marked symptom-specific anti-depressant effect of MFB-DBS was demonstrated. The ICSS-paradigm revealed that MFB-DBS, as opposed to vmPFC-DBS interacts with the reward system. CONCLUSION: Our data suggest that MFB-DBS and Cg25-DBS do not operate via the same neurobiological circuits. This differentiation might be of interest when selecting patients for either Cg25- or MFB-DBS.

Social experience modulates ocular dominance plasticity differentially in adult male and female mice.

Environmental factors have long been known to regulate brain plasticity. We investigated the potential influence of social experience on ocular dominance plasticity. Fully adult female or male mice were monocularly deprived for four days and kept a) either alone or in pairs of the same sex and b) either in a small cage or a large, featureless arena. While mice kept alone did not show ocular dominance plasticity, no matter whether in a cage or in an arena, paired female mice in both environmental conditions displayed a shift of ocular dominance towards the open eye. Paired male mice, in contrast, showed no plasticity in the cage, but a very strong ocular dominance shift in the arena. This effect was not due to increased locomotion, since the covered distance was similar in single and paired male mice in the arena, and furnishing cages with a running wheel did not enable ocular dominance plasticity in cage-housed mice. Confirming recent results in rats, the plasticity-enhancing effect of the social environment was shown to be mediated by serotonin. Our results demonstrate that social experience has a strong effect on cortical plasticity that is sex-dependent. This has potential consequences both for animal research and for human education and rehabilitation.

Stress in puberty unmasks latent neuropathological consequences of prenatal immune activation in mice.

Prenatal infection and exposure to traumatizing experiences during peripuberty have each been associated with increased risk for neuropsychiatric disorders. Evidence is lacking for the cumulative impact of such prenatal and postnatal environmental challenges on brain functions and vulnerability to psychiatric disease. Here, we show in a translational mouse model that combined exposure to prenatal immune challenge and peripubertal stress induces synergistic pathological effects on adult behavioral functions and neurochemistry. We further demonstrate that the prenatal insult markedly increases the vulnerability of the pubescent offspring to brain immune changes in response to stress. Our findings reveal interactions between two adverse environmental factors that have individually been associated with neuropsychiatric disease and support theories that mental illnesses with delayed onsets involve multiple environmental hits.