Preclinical Model to Evaluate Outcomes of Amyloid Cross-Toxicity in the Rodent Brain.

The progress of neurodegenerative disorders correlates with the spread of their associated amyloidogenic proteins. Here, we investigated whether amyloid entry into nonconstitutive neurons could drive cross-toxic outcomes. Amyloid ß (Aß) was stereotaxically introduced into the rodent midbrain tegmentum, where it is not endogenously expressed. Postinfusion, rodent motor and sensorimotor capacities were assessed by standard behavioral tests at 3, 6, 9, and 12 months. The longitudinal study revealed no behavioral abnormalities. However, Aß insult provoked intraneuronal inclusions positive for phosphorylated α-synuclein in dopaminergic neurons and were seen throughout the midbrain, a pathognomonic biomarker suggesting Parkinson's pathogenesis. These findings not only underscore the cross-toxic potential of amyloid proteins but also provide a mechanism by which they disrupt homeostasis in nonconstitutive neurons and cause neuronal corruption, injury, and demise. This study may help reconcile the large incidence of neurodegenerative comorbidity observed clinically.

Electrical Stimulation Evokes Rotational Behavior In Tandem with Exocytotic-like Increases in Dopamine Measured by In Vivo Intracerebral Microdialysis.

BACKGROUND: Electrical Stimulation is a traditional tool in neuroscience and is commonly used in vivo to evoke behavior and in vitro to study neural mechanisms. In vivo intracerebral microdialysis, also a traditional technique, is used to assay neurotransmitter release. However, the combination of these techniques is highly limited to studies using anesthetized animals; therefore, evoking and measuring exocytotic neurotransmitter release in awake models is lacking. Combining these techniques in an awake animal preparation is presented here with evidence to support the mechanistic action of electrical stimulation in vivo. NEW METHODS: This report presents converging evidence to validate the combination of intracerebral electrical stimulation with microdialysis as a novel procedure to study exocytotic-like dopamine release in behaving animals. RESULTS: It is shown that electrical stimulation of the medial forebrain bundle can be used to evoke frequency- and intensity-dependent exocytotic-like dopamine overflow and rotational behavior that are sensitive to Na+ channel blockade and Ca++ availability. COMPARISON WITH EXISTING METHODS: Studies using modern techniques to evoke neurotransmitter release, combined with in vivo intracerebral microdialysis, and measured behavioral output are scarce. In contrast, commonly used pharmacological methods often are less precise and inefficient to evoke exocytotic dopamine release and behavior. Here we demonstrate, the combination of in vivo intracerebral microdialysis with electrical stimulation as a simple approach to simultaneously assess physiologically relevant neurotransmitter 'release' and behavior. CONCLUSIONS: Research that aims to understand how dopamine neurotransmission is altered in behavioral disorders can utilize this innovative combination of electrical stimulation with in vivo intracerebral microdialysis.

Testing Amyloid Cross-Toxicity in the Vertebrate Brain.

While amyloid proteins such as amyloid ß (Aß),α-synuclein, tau, and lysozyme are known to be prion-like; emerging data have revealed that they are also able to seed the misfolding of prion-like proteins differing in sequence. In the present study, we have developed a tool designed to test neurohistochemical outcomes associated with the entry of an amyloid protein into heterotypic neurons, i.e., neurons that do not express the invading amyloid and, instead, endogenously express amyloids differing in sequence. The stereotaxic introduction of Aß into the rodent tegmental area of the mid-brain revealed that the foreign amyloid had infiltrated into nigral neurons. Furthermore, Aß was found colocalized with α-synuclein, an amyloid endogenous to the substantia nigra and differing in sequence relative to Aß. Disruption of α-synuclein status in the substantia nigra is associated with Parkinson's disease onset and progress. In addition to the study findings, a significant inroad to future neurodegenerative research was made via the stereotaxic introduction of the foreign amyloid. This technique limits the presence of confounding neurometabolic variables that may be prevalent in transgenic animal models of cross-toxicity and, thereby, better addresses the role of individual neuronal factors in cross-toxicity. Finally, the data from this work may help reconcile the high frequency of clinical comorbidity seen in neurodegenerative diseases.

The Global Challenge in Neuroscience Education and Training: The MBL Perspective.

The greatest challenge in moving neuroscience research forward in the 21st century is recruiting, training, and retaining the brightest, rigorous, and most diverse scientists. The MBL research training courses Neurobiology and Neural Systems & Behavior, and the Summer Program in Neuroscience, Excellence, and Success provide a model for full immersion, discovery-based training while enhancing cultural, geographic, and racial diversity.

Beta frequency synchronization in basal ganglia output during rest and walk in a hemiparkinsonian rat.

Synchronized oscillatory neuronal activity in the beta frequency range has been observed in the basal ganglia of Parkinson's disease patients and hypothesized to be antikinetic. The unilaterally lesioned rat model of Parkinson's disease allows examination of this hypothesis by direct comparison of beta activity in basal ganglia output in non-lesioned and dopamine cell lesioned hemispheres during motor activity. Bilateral substantia nigra pars reticulata (SNpr) recordings of units and local field potentials (LFP) were obtained with EMG activity from the scapularis muscle in control and unilaterally nigrostriatal lesioned rats trained to walk on a rotary treadmill. After left hemispheric lesion, rats had difficulty walking contraversive on the treadmill but could walk in the ipsiversive direction. During inattentive rest, SNpr LFP power in the 12-25 Hz range (low beta) was significantly greater in the dopamine-depleted hemisphere than in non-lesioned and control hemispheres. During walking, low beta power was reduced in all hemispheres, while 25-40 Hz (high beta) activity was selectively increased in the lesioned hemisphere. High beta power increases were reduced by l-DOPA administration. SNpr spiking was significantly more synchronized with SNpr low beta LFP oscillations during rest and high beta LFP oscillations during walking in the dopamine-depleted hemispheres compared with non-lesioned hemispheres. Data show that dopamine loss is associated with opposing changes in low and high beta range SNpr activity during rest and walk and suggest that increased synchronization of high beta activity in SNpr output from the lesioned hemisphere during walking may contribute to gait impairment in the hemiparkinsonian rat.

A history of human-like dieting alters serotonergic control of feeding and neurochemical balance in a rat model of binge-eating.

OBJECTIVE: This study replicated a model of stress-induced binge-eating in rats with a history of caloric restriction (HCR), tested their response to SSRI (fluoxetine) treatment, and explored changes in brain monoamine levels. METHOD: Young female rats with no-HCR/no-Stress, no-HCR/Stress, HCR/no-Stress, and HCR+Stress (binge-eating) were treated with fluoxetine. Post-mortem levels of serotonin, dopamine, and metabolites were assessed from brain regions key to feeding and reward. RESULTS: A 3 mg/kg dose of fluoxetine without effect in the no-HCR groups suppressed intake of HCR groups, normalizing the binge-eating of HCR/Stress rats. No differences in monoamines were detected in the hypothalamus or tegmentum but a strong positive relationship between accumbens serotonin and dopamine turnover in no-HCR rats was absent in rats with HCR. CONCLUSION: Despite lack of hunger, a history of human-like dieting alters serotonin function in ways suggesting consequences not only to feeding but also control of reward and mood that are dependent on dopamine/serotonin interactions.

Biological research on drug abuse and addiction in Hispanics: current status and future directions.

Impressive progress has been made in the understanding of biological contributions to drug abuse and addiction. An area that has only recently begun to receive attention is potential ethnic and racial differences in biological systems that contribute to, or protect from, problem drug use. This article reviews recent research on drug abuse and addiction in Hispanics in which biological questions have been addressed, including work on genes, gene products (proteins), physiology and pharmacotherapy. Taken together, work to date suggests that there are both similarities and differences between Hispanics and other ethnic groups in biological factors related to drug abuse and addiction. Although the results are intriguing, relatively few studies have been done, and those that have been done have often been inconclusive due to low numbers of Hispanic subjects. Moreover, studies have often failed to recognize the complexity and heterogeneity of Hispanic populations in the United States and around the world. After reviewing the current status of the field, recommendations are given for future research in both humans and relevant animal models that will lead to a better understanding of drug abuse and addiction in Hispanics.