The translation of basic behavioral science discoveries into practical strategies represents a promising approach to developing more effective preventive interventions to improve health. Since ...translational research inevitably involves making use of diverse perspectives from multiple disciplines, it is best conducted as a transdisciplinary enterprise. In this paper, we discuss current strategies used by NIH to support transdisciplinary translational behavioral (TDTB) research, summarize successful efforts, and highlight challenges encountered in conducting such work (ranging from conceptual to organizational to methodological). Using examples from NIH-funded projects we illustrate the potential benefits of, and barriers to, pursuing this type of research and discuss next steps and potential future directions for NIH-supported TDTB research.
Neuroplasticity can be defined as the ability of the nervous system to respond to intrinsic or extrinsic stimuli by reorganizing its structure, function and connections. Major advances in the ...understanding of neuroplasticity have to date yielded few established interventions. To advance the translation of neuroplasticity research towards clinical applications, the National Institutes of Health Blueprint for Neuroscience Research sponsored a workshop in 2009. Basic and clinical researchers in disciplines from central nervous system injury/stroke, mental/addictive disorders, paediatric/developmental disorders and neurodegeneration/ageing identified cardinal examples of neuroplasticity, underlying mechanisms, therapeutic implications and common denominators. Promising therapies that may enhance training-induced cognitive and motor learning, such as brain stimulation and neuropharmacological interventions, were identified, along with questions of how best to use this body of information to reduce human disability. Improved understanding of adaptive mechanisms at every level, from molecules to synapses, to networks, to behaviour, can be gained from iterative collaborations between basic and clinical researchers. Lessons can be gleaned from studying fields related to plasticity, such as development, critical periods, learning and response to disease. Improved means of assessing neuroplasticity in humans, including biomarkers for predicting and monitoring treatment response, are needed. Neuroplasticity occurs with many variations, in many forms, and in many contexts. However, common themes in plasticity that emerge across diverse central nervous system conditions include experience dependence, time sensitivity and the importance of motivation and attention. Integration of information across disciplines should enhance opportunities for the translation of neuroplasticity and circuit retraining research into effective clinical therapies.
Dopamine D3 receptors have been implicated in pathophysiological substrates of schizophrenia, and neuroleptic drugs which are antagonists primarily at D2 receptors possess therapeutic activity in ...this disorder. In the present study, rats tested for hypomotility induced by 7-hydroxy-DPAT (7OH, a selective D3 agonist) were pretreated with the neuroleptic haloperidol. These animals showed an attenuated agonist-induced suppression of behavior compared with rats receiving 7OH alone. The drug combination also 'normalized' dopamine metabolism in the frontal cortex, as turnover ratios which are typically enhanced by acute neuroleptic administration were no longer significantly increased when 7OH was also given. These observations suggest that the effects of haloperidol in cortical regions regulating limbic locomotor systems may be important for therapeutic efficacy in schizophrenic symptoms generated from a D3 substrate.
Animals in the present investigation were trained for conditioned place preference by pairing the non-preferred compartment of a two chamber apparatus with either 1.5 mg kg-1 D-amphetamine or 0.05 mg ...kg-1 scopolamine. Some of the amphetamine-conditioned rats were injected with 0.05 mg kg-1 scopolamine as an acute treatment on the test day which followed conditioning. Although the scopolamine by itself did not induce either a preference or an aversion to the drug-paired side, it enhanced the expression of place preference in animals conditioned with amphetamine. Potentiation of this conditioned response (CR) was observed in the absence of changes in locomotor activation which would implicate general arousal as a potential mechanism. Hypotheses regarding anticholinergic mediation of CR expression via central reward mechanisms, memory retrieval, cue function and stimulus saliency are discussed, and possible neurosubstrates considered.
1.
1. Negative symptoms of schizophrenia are characterized by amotivation, anhedonia and anergia. These aspects of the symptom profile can be modeled by D3 agonism in animal behavioral models.
2.
2. ...Serotonergic systems have been implicated in pathophysiologic substrates for this disorder; most notably, in deficit state schizophrenia, as newer ‘atypical’ neuroleptics which are especially efficacious for treating this syndrome antagonize central 5-HT2 receptors.
3.
3. FC regions may also be important in chronic negative symptoms, as hypofrontality has been associated with these schizophrenic features.
4.
4. The author examined effects of a behaviorally-active dose of the D3 agonist, 7OH, on 5-HT metabolism in FC, and the ability of a low-dose neuroleptic treatment to antagonize this biochemical effect.
5.
5. Acute administration of 7OH induced a selective decrease of 5-HT turnover in the FC without affecting metabolism of this transmitter in more subcortical DA regions.
6.
6. Hal, which has previously been demonstrated to antagonize electrophysiologic, biochemical and behavioral effects of 7OH, was without effect on agonist-induced decreases in 5-HT turnover.
7.
7. The biochemical association between D3 agonism and reductions of FC 5-HT may be significant for pathophysiologic mechanisms of negative symptoms, and antagonism of this effect may differ for neuroleptics with varying efficacy in alleviating these symptoms.
Negative symptoms have been associated with structural impairment in the PFC, and hypothesized to arise from a central hypodopaminergic substrate. Corticofugal PFC neurons, which are inhibited by VTA ...DA innervation, exert a tonic excitatory modulation on DA activity in the NAS. Lesions of ascending DA forebrain projections "uncouple" the functional link between D1 and D2 receptors, permitting independent activation of D1 sites in generating behavioral output. A previously identified absence of this D1/D2 link in schizophrenic brain suggests that functional activation of PFC D1 receptors may induce hyperinhibition of descending corticofugal efferents to the NAS. Consequent hypoactivity of DA in the NAS is proposed to give rise to negative symptoms of schizophrenia, and low dose DA agonist treatments may mimic behavioral features of this symptom profile via direct PFC D1 stimulation. It follows that clozapine's efficacy for negative symptoms may be attributable, in part, to blockade of PFC D1 receptors, with subsequent enhancement of glutamate-facilitated NAS DA activity.
PDF
