Expression of the Neuregulin Receptor ErbB4 in the Brain of the Rhesus Monkey (Macaca mulatta)

We demonstrated recently that frontal cortical expression of the Neuregulin (NRG) receptor ErbB4 is restricted to interneurons in rodents, macaques, and humans. However, little is known about protein expression patterns in other areas of the brain. In situ hybridization studies have shown high ErbB4 mRNA levels in various subcortical areas, suggesting that ErbB4 is also expressed in cell types other than cortical interneurons. Here, using highly-specific monoclonal antibodies, we provide the first extensive report of ErbB4 protein expression throughout the cerebrum of primates. We show that ErbB4 immunoreactivity is high in association cortices, intermediate in sensory cortices, and relatively low in motor cortices. The overall immunoreactivity in the hippocampal formation is intermediate, but is high in a subset of interneurons. We detected the highest overall immunoreactivity in distinct locations of the ventral hypothalamus, medial habenula, intercalated nuclei of the amygdala and structures of the ventral forebrain, such as the islands of Calleja, olfactory tubercle and ventral pallidum, and medium expression in the reticular thalamic nucleus. While this pattern is generally consistent with ErbB4 mRNA expression data, further investigations are needed to identify the exact cellular and subcellular sources of mRNA and protein expression in these areas. In contrast to in situ hybridization in rodents, we detected only low levels of ErbB4-immunoreactivity in mesencephalic dopaminergic nuclei but a diffuse pattern of immunofluorescence that was medium in the dorsal striatum and high in the ventral forebrain, suggesting that most ErbB4 protein in dopaminergic neurons could be transported to axons. We conclude that the NRG-ErbB4 signaling pathway can potentially influence many functional systems throughout the brain of primates, and suggest that major sites of action are areas of the “corticolimbic” network. This interpretation is functionally consistent with the genetic association of NRG1 and ERBB4 with schizophrenia

Noncanonical function of an autophagy protein prevents spontaneous Alzheimer’s disease

Noncanonical functions of autophagy proteins have been implicated in neurodegenerative conditions, including Alzheimer’s disease (AD). The WD domain of the autophagy protein Atg16L is dispensable for canonical autophagy but required for its noncanonical functions. Two-year-old mice lacking this domain presented with robust β-amyloid (Aβ) pathology, tau hyperphosphorylation, reactive microgliosis, pervasive neurodegeneration, and severe behavioral and memory deficiencies, consistent with human disease. Mechanistically, we found this WD domain was required for the recycling of Aβ receptors in primary microglia. Pharmacologic suppression of neuroinflammation reversed established memory impairment and markers of disease pathology in this novel AD model. Therefore, loss of the Atg16L WD domain drives spontaneous AD in mice, and inhibition of neuroinflammation is a potential therapeutic approach for treating neurodegeneration and memory loss. A decline in expression of ATG16L in the brains of human patients with AD suggests the possibility that a similar mechanism may contribute in human disease

Long-term effects of a single adult methamphetamine challenge: Minor impact on dopamine fibre density in limbic brain areas of gerbils

BACKGROUND: The aim of the study was to test long-term effects of (+)-methamphetamine (MA) on the dopamine (DA) innervation in limbo-cortical regions of adult gerbils, in order to understand better the repair and neuroplasticity in disturbed limbic networks. METHODS: Male gerbils received a single high dose of either MA (25 mg/kg i.p.) or saline on postnatal day 180. On postnatal day 340 the density of immunoreactive DA fibres and calbindin and parvalbumin cells was quantified in the right hemisphere. RESULTS: No effects were found in the prefrontal cortex, olfactory tubercle and amygdala, whereas the pharmacological impact induced a slight but significant DA hyperinnervation in the nucleus accumbens. The cell densities of calbindin (CB) and parvalbumin (PV) positive neurons were additionally tested in the nucleus accumbens, but no significant effects were found. The present results contrast with the previously published long-term effects of early postnatal MA treatment that lead to a restraint of the maturation of DA fibres in the nucleus accumbens and prefrontal cortex and a concomitant overshoot innervation in the amygdala. CONCLUSION: We conclude that the morphogenetic properties of MA change during maturation and aging of gerbils, which may be due to physiological alterations of maturing vs. mature DA neurons innervating subcortical and cortical limbic areas. Our findings, together with results from other long-term studies, suggest that immature limbic structures are more vulnerable to persistent effects of a single MA intoxication; this might be relevant for the assessment of drug experience in adults vs. adolescents, and drug prevention programs

Environmental enrichment has no effect on the development of dopaminergic and GABAergic fibers during methylphenidate treatment of early traumatized gerbils

It is widely believed, that environmental factors play a crucial role in the etiology and outcome of psychiatric diseases such as Attention-Deficit/Hyperactivity Disorder (ADHD). A former study from our laboratory has shown that both methylphenidate (MP) and handling have a positive effect on the dopaminergic fiber density in the prefrontal cortex (PFC) of early traumatized gerbils (Meriones unguiculatus). The current study was performed to investigate if enriched environment during MP application has an additional influence on the dopaminergic and GABAergic fiber densities in the PFC and amygdala in this animal model

Neuropathology of aging in cats and its similarities to human Alzheimer’s disease

Elderly cats develop age-related behavioral and neuropathological changes that ultimately lead to cognitive dysfunction syndrome (CDS). These neuropathologies share similarities to those seen in the brains of humans with Alzheimer’s disease (AD), including the extracellular accumulation of ß-amyloid (Aβ) and intraneuronal deposits of hyperphosphorylated tau, which are considered to be the two major hallmarks of AD. The present study assessed the presence and distribution of Aβ and tau hyperphosphorylation within the cat brain (n = 55 cats), and how the distribution of these proteins changes with age and the presence of CDS. For this, immunohistochemistry was performed on seven brain regions from cats of various ages, with and without CDS (n = 10 with CDS). Cats accumulate both intracytoplasmic and extracellular deposits of Aβ, as well as intranuclear and intracytoplasmic hyperphosphorylated tau deposits. Large extracellular aggregates of Aβ were found in elderly cats, mainly in the cortical brain areas, with occasional hippocampal aggregates. This may suggest that these aggregates start in cortical areas and later progress to the hippocampus. While Aβ senile plaques in people with AD have a dense core, extracellular Aβ deposits in cats exhibited a diffuse pattern, similar to the early stages of plaque pathogenesis. Intraneuronal Aβ deposits were also observed, occurring predominantly in cortical brain regions of younger cats, while older cats had few to no intraneuronal Aβ deposits, especially when extracellular aggregates were abundant. Intracytoplasmic hyperphosphorylated tau was found within neurons in the brains of elderly cats, particularly in those with CDS. Due to their ultrastructural features, these deposits are considered to be pre-tangles, which are an early stage of the neurofibrillary tangles seen in AD. The largest numbers of pre-tangles are found mainly in the cerebral cortex of elderly cats, whereas lower numbers were found in other regions (i.e., entorhinal cortex and hippocampus). For the first time, intranuclear tau was found in both phosphorylated and non-phosphorylated states within neurons in the cat brain. The highest numbers of intranuclear deposits were found in the cortex of younger cats, and this tended to decrease with age. In contrast, elderly cats with pre-tangles had only occasional or no nuclear labelling

Translating advances in the molecular basis of schizophrenia into novel cognitive treatment strategies

The presence and severity of cognitive symptoms, including working memory, executive dysfunction and attentional impairment, contributes materially to functional impairment in schizophrenia. Cognitive symptoms have proven resistant to both first- and second-generation antipsychotic drugs. Efforts to develop a consensus set of cognitive domains that are both disrupted in schizophrenia and are amenable to cross-species validation (e.g. the NIMH CNTRICS and RDoC initiatives) are an important step towards standardisation of outcome measures that can used in preclinical testing of new drugs. While causative genetic mutations have not been identified, new technologies have identified novel genes as well as hitherto candidate genes previously implicated in the pathophysiology of schizophrenia and/or mechanisms of antipsychotic efficacy. This review comprises a selective summary of these developments, particularly phenotypic data arising from preclinical genetic models for cognitive dysfunction in schizophrenia, with the aim of indicating potential new directions for pro-cognitive therapeutics

Love as the Reason and Limit of Freedom and the Church as “No Man’s Land” in the Midst of Society: A European Perspective

Western societies are polarizing and are coming under pressure from within and without. Unresolved global threats such as the ecological crisis and the scarcity of resources are accompanied by a new complexity of political powers. At the same time, the forces of social cohesion, which had long proved to be based on a mix of enlightened rationality and Christian values, are eroding. Where does the church stand in this situation? Does it become an actor alongside others in the struggle for cultural dominance? Or does it succeed in finding its place anew? What does it mean for its place in society if the mission of its preaching is not to secure a particular society, however, it is imagined, but to call sinners out of the bonds of death into the freedom of the justified children of God? This sectional will explore suggestions from the Lutheran theologian Hans Joachim Iwand (1899-1960), who in the 1950s, in the face of the ethical-cultural devastation after National Socialism, asked what Christians could contribute to the well-being and freedom of a life-serving political community