Volume 24, Issue 2

Parkinson’s disease is the most common neurodegenerative movement disorder. The motor impairments of Parkinson’s disease are caused by the loss of dopaminergic neurons in the substantia nigra and associated with the appearance of fibrillar aggregates of α-synuclein (α-syn) called Lewy bodies. Approximately 90% of α-syn deposited in Lewy bodies is phosphorylated at serine 129 (Ser129). In contrast, only 4% or less of total α-syn is phosphorylated at this residue in the normal brain. This suggests that the accumulation of Ser129-phosphorylated α-syn leads to the formation of Lewy bodies and dopaminergic neurodegeneration in Parkinson’s disease. Our laboratory and others have performed experiments using in vivo models of Parkinson’s disease to elucidate the role of increased Ser129 phosphorylation in α-syn neurotoxicity. However, there has been a lack of consistency among these models. In this review, we summarize the main findings regarding the relationship between Ser129 phosphorylation and α-syn neurotoxicity, and examine the differences among models. We further discuss the role of Ser129 phosphorylation in α-syn aggregation and the future directions to test the potential of Ser129 phosphorylation as a therapeutic target for slowing the progression of Parkinson’s disease.

Because the complex functions of the basal ganglia have been increasingly studied over the past several decades, the understanding of the role of the subthalamic nucleus (STN) in motor and cognitive functions has evolved. The traditional role in motor function ascribed to the STN, based on its involvement in the cortico-striato-thalamo-cortical motor loops, the pathologic STN activity seen in Parkinson’s disease, and the benefits in motor symptoms following STN lesions and deep brain stimulation, has been revised to include wider cognitive functions. The increased attention focused on such nonmotor functions housed within the STN partially arose from the observed cognitive and affective side effects seen with STN deep brain stimulation. The multiple modalities of research have corroborated these findings and have provided converging evidence that the STN is critically involved in cognitive processes. In particular, numerous experiments have demonstrated the involvement of the STN in high-conflict decisions. The different STN functions appear to be related to activity in anatomically distinct subregions, with the ventral STN contributing to high-conflict decision-making through its role in the hyperdirect pathway involving the prefrontal cortex.

Parkinson’s disease (PD) is a common, disabling, neurodegenerative condition, and the disease prevalence is expected to increase worldwide in the next few decades. Symptomatic therapy remains unsatisfactory, and greatly needed neuroprotective therapies have not been successfully developed so far. Physical exercise (PE) has been associated with a lower risk of developing a neurodegenerative disease. The literature has been searched, and results have been systematized and interpreted with regard to the effects of PE in PD. Published data show the following: 1) PE has been associated with a lower risk of developing PD; 2) PE has been shown to improve disease symptoms, mobility, balance, gait and quality of life (in this regard, walking training, tai-chi and tango dancing have demonstrated the highest level of evidence of efficacy); and 3) neuroprotective effects from PE could be expected in PD, although this has been suggested in animal studies only. Further research on this topic should be encouraged. Multidisciplinary cooperation between neurologists, sports physicians and researchers is paramount.

Treatment with the classic antipsychotic drugs (APDs), such as haloperidol (HAL), is associated with both acute and chronic motor side effects. Acutely, these drugs may induce extrapyramidal symptoms, whereas a prolonged treatment may result in tardive dyskinesia (TD). Atypical antipsychotics have a lower incidence of motor side effects, which have been partially ascribed to the antagonism of serotonin (5-HT) receptors. Although there is currently no satisfactory pharmacotherapy for TD, deep brain stimulation (DBS) has emerged as a promising therapy. However, the mechanisms underlying its effects remain largely unknown. DBS has been shown to affect several neurotransmitter systems, including 5-HT. In this review, we outline the involvement of 5-HT in the development of HAL-induced catalepsy and TD. We also discuss the evidence for DBS-induced alterations in 5-HT function and the relevance of serotonergic alterations to the antidyskinetic effects of DBS. The evidence suggests that the serotonergic mechanisms may be involved in the acute and chronic motor side effects of APDs as well as in adverse psychiatric effects that have been reported following DBS. However, the current evidence suggests that 5-HT alterations do not play an important role in the effectiveness of DBS in models of dyskinesias induced by chronic APDs.

The emotion of anxiety represents one of the most studied topics in the neurosciences, in part due to its relevance for understanding the evolutionary development of the human brain and its role in the pathogenesis of psychopathological conditions. Structural magnetic resonance imaging (sMRI) has enabled mapping of the anxious human brain and has contributed substantially to the understanding of anxiety. Alongside the fields of clinical psychology/psychiatry, personality psychology aims to support the research endeavor of mapping the anxious brain and has found that individual differences in anxiety-related personality dimensions such as Neuroticism or Harm Avoidance (measured by self-report) are correlated with gray and white matter volumes in different areas of the human brain. This review reveals that structures including parts of the frontal cortex (e.g., the orbitofrontal cortex) and the temporal lobe (e.g., the hippocampus) are often associated with trait anxiety, and it points out the inconsistencies that exist in the personality-sMRI literature on human anxiety. Consequently, we suggest new research strategies to overcome the inconsistencies. This review outlines how results from animal research can guide scientists in developing testable hypotheses in search of the anxious brain. Moreover, genetic imaging is presented as an interesting approach to mapping the anxious brain.

Among an impressive variety of identified serotonin receptors, 5-HT 1A attracts particular attention due to its central role in the regulation of 5-HT-ergic neurotransmission and the data on its involvement in the mechanisms of stress response, aggressive behavior, anxiety, and depression. This review concentrates on the cross-regulation between 5-HT receptors and the implication of the 5-HT 1A receptor in the genetic control of 5-HT-related behavior. Specifically, it describes the (1) functional interactions between 5-HT 1A , 5-HT 2A , 5-HT 3 , and 5-HT 7 receptors; (2) cross-talk between 5-HT 1A receptor and genes encoding key members of the brain 5-HT system; (3) implication of the 5-HT 1A receptor in natural hibernation and genetic predisposition to different kinds of defensive behavior; and (4) role of 5 - HT 1A autoreceptors and heteroreceptors in anxiety, depression, and suicide, and in the antidepressant effect of serotonin reuptake inhibitors. This review provides converging lines of evidence that the 5-HT 1A receptor contributes to the action of other 5-HT receptors, modulating their effect on behavior, and describes new data on the unique role of the 5-HT 1A receptor in the indirect regulation of gene expression and in the autoregulation of the brain 5-HT system.

Irradiation in the red/near-infrared spectrum (R/NIR, 630–1000 nm) has been used to treat a wide range of clinical conditions, including disorders of the central nervous system (CNS), with several clinical trials currently underway for stroke and macular degeneration. However, R/NIR irradiation therapy (R/NIR-IT) has not been widely adopted in clinical practice for CNS injury or disease for a number of reasons, which include the following. The mechanism/s of action and implications of penetration have not been thoroughly addressed. The large range of treatment intensities, wavelengths and devices that have been assessed make comparisons difficult, and a consensus paradigm for treatment has not yet emerged. Furthermore, the lack of consistent positive outcomes in randomised controlled trials, perhaps due to sub-optimal treatment regimens, has contributed to scepticism. This review provides a balanced précis of outcomes described in the literature regarding treatment modalities and efficacy of R/NIR-IT for injury and disease in the CNS. We have addressed the important issues of specification of treatment parameters, penetration of R/NIR irradiation to CNS tissues and mechanism/s, and provided the necessary detail to demonstrate the potential of R/NIR-IT for the treatment of retinal degeneration, damage to white matter tracts of the CNS, stroke and Parkinson’s disease.

Stress is a complex biological reaction common to all living organisms that allows them to adapt to their environments. Chronic stress alters the dendritic architecture and function of the limbic brain areas that affect memory, learning, and emotional processing. This review summarizes our research about chronic stress effects on the auditory system, providing the details of how we developed the main hypotheses that currently guide our research. The aims of our studies are to (1) determine how chronic stress impairs the dendritic morphology of the main nuclei of the rat auditory system, the inferior colliculus (auditory mesencephalon), the medial geniculate nucleus (auditory thalamus), and the primary auditory cortex; (2) correlate the anatomic alterations with the impairments of auditory fear learning; and (3) investigate how the stress-induced alterations in the rat limbic system may spread to nonlimbic areas, affecting specific sensory system, such as the auditory and olfactory systems, and complex cognitive functions, such as auditory attention. Finally, this article gives a new evolutionary approach to understanding the neurobiology of stress and the stress-related disorders.