Dopaminergic Innervation Research Articles

Implications of Developmental 17-OHPC Exposure on the Mesocorticolimbic Serotonergic and Dopaminergic Pathways and Adolescent Mood-Related Behavior in Rats.

The synthetic progestin, 17-α-hydroxyprogesterone caproate (17-OHPC), is administered to pregnant individuals at risk for recurrent preterm birth during a critical period of fetal mesocorticolimbic serotonergic and dopaminergic pathway development. These pathways play an important role in regulating cognitive behaviors later in life. Despite this, there has been very little research regarding the potential long-term effects of 17-OHPC on the behavioral and neural development of exposed children. In rodents, developmental exposure to 17-OHPC disrupts serotonergic and dopaminergic innervation of the medial prefrontal cortex and impairs decision-making in complex cognitive tasks in adulthood. The present study tested the hypothesis that developmental exposure to 17-OHPC similarly disrupts the development of serotonergic and dopaminergic pathways within limbic targets and subsequent mood-related behaviors. Developmental 17-OHPC exposure significantly increased the density of serotonin transporter-IR fibers in CA1, CA2/3, and the suprapyramidal blade of dentate gyrus in hippocampus and significantly reduced the density of TH-IR fibers within the nucleus accumbens shell in males but had no effect in females during adolescence. Irregular microglia activational phenotype and number were also observed in the hippocampus of 17-OHPC-exposed males. Developmental 17-OHPC reduced the latency to immobility in males in the forced swim test but did not affect sucrose consumption in a sucrose preference test. These findings suggest that 17-OHPC exerts sex-specific effects on the development of mesocorticolimbic pathways and mood-related behavior in adolescence and highlight the need to investigate effects in adolescent children.

The history and status of dopamine cell therapies for Parkinson's disease.

Parkinson's disease (PD) is characterized by the loss of the dopaminergic nigrostriatal pathway which has led to the successful development of drug therapies that replace or stimulate this network pharmacologically. Although these drugs work well in the early stages of the disease, over time they produce side effects along with less consistent clinical benefits to the person with Parkinson's (PwP). As such there has been much interest in repairing this pathway using transplants of dopamine neurons. This work which began 50 years ago this September is still ongoing and has now moved to first in human trials using human pluripotent stem cell-derived dopaminergic neurons. The results of these trials are eagerly awaited although proof of principle data has already come from trials using human fetal midbrain dopamine cell transplants. This data has shown that developing dopamine cells when transplanted in the brain of a PwP can survive long term with clinical benefits lasting decades and with restoration of normal dopaminergic innervation in the grafted striatum. In this article, we discuss the history of this field and how this has now led us to the recent stem cell trials for PwP.

Dissociable effects of dopaminergic medications on depression symptom dimensions in Parkinson disease

Depression in Parkinson disease (PD) is common, is disabling and responds poorly to standard antidepressants. Motivational symptoms of depression are particularly prevalent in PD and emerge with loss of dopaminergic innervation of the striatum. Optimizing dopaminergic treatment for PD can improve depressive symptoms. However, the differential effect of antiparkinsonian medication on symptom dimensions of depression is not known. Using data from a large (n = 412) longitudinal study of patients with newly diagnosed PD followed over 5 years, we investigated whether there are dissociable effects of dopaminergic medications on different depression symptom dimensions in PD. Previously validated ‘motivation’ and ‘depression’ dimensions were derived from the 15-item geriatric depression scale. Dopaminergic neurodegeneration was measured using repeated striatal dopamine transporter imaging. We identified dissociable associations between dopaminergic medications and different dimensions of depression in PD. Dopamine agonists were shown to be effective for treatment of motivational symptoms of depression. In contrast, monoamine oxidase-B inhibitors improved both depressive and motivation symptoms, albeit the latter effect is attenuated in patients with more severe striatal dopaminergic neurodegeneration.

Dopamine neuron degeneration in the Ventral Tegmental Area causes hippocampal hyperexcitability in experimental Alzheimer’s Disease

Early and progressive dysfunctions of the dopaminergic system from the Ventral Tegmental Area (VTA) have been described in Alzheimer’s Disease (AD). During the long pre-symptomatic phase, alterations in the function of Parvalbumin interneurons (PV-INs) are also observed, resulting in cortical hyperexcitability represented by subclinical epilepsy and aberrant gamma-oscillations. However, it is unknown whether the dopaminergic deficits contribute to brain hyperexcitability in AD. Here, using the Tg2576 mouse model of AD, we prove that reduced hippocampal dopaminergic innervation, due to VTA dopamine neuron degeneration, impairs PV-IN firing and gamma-waves, weakens the inhibition of pyramidal neurons and induces hippocampal hyperexcitability via lower D2-receptor-mediated activation of the CREB-pathway. These alterations coincide with reduced PV-IN numbers and Perineuronal Net density. Importantly, L-DOPA and the selective D2-receptor agonist quinpirole rescue p-CREB levels and improve the PV-IN-mediated inhibition, thus reducing hyperexcitability. Moreover, similarly to quinpirole, sumanirole – another D2-receptor agonist and a known anticonvulsant – not only increases p-CREB levels in PV-INs but also restores gamma-oscillations in Tg2576 mice. Conversely, blocking the dopaminergic transmission with sulpiride (a D2-like receptor antagonist) in WT mice reduces p-CREB levels in PV-INs, mimicking what occurs in Tg2576. Overall, these findings support the hypothesis that the VTA dopaminergic system integrity plays a key role in hippocampal PV-IN function and survival, disclosing a relevant contribution of the reduced dopaminergic tone to aberrant gamma-waves, hippocampal hyperexcitability and epileptiform activity in early AD.

Dysregulation of the dopaminergic system secondary to traumatic brain injury: implications for mood and anxiety disorders.

Traumatic brain injury (TBI) represents a public health issue with a high mortality rate and severe neurological and psychiatric consequences. Mood and anxiety disorders are some of the most frequently reported. Primary and secondary damage can cause a loss of neurons and glial cells, leading to dysfunction of neuronal circuits, which can induce imbalances in many neurotransmitter systems. Monoaminergic systems, especially the dopaminergic system, are some of the most involved in the pathogenesis of neuropsychiatric and cognitive symptoms after TBI. In this work, we summarize the studies carried out in patients who have suffered TBI and describe alterations in the dopaminergic system, highlighting (1) dysfunction of the dopaminergic neuronal circuits caused by TBI, where modifications are shown in the dopamine transporter (DAT) and alterations in the expression of dopamine receptor 2 (D2R) in brain areas with dopaminergic innervation, thus establishing a hypodopaminergic state and (2) variations in the concentration of dopamine and its metabolites in biological fluids of post-TBI patients, such as elevated dopamine (DA) and alterations in homovanillic acid (HVA). On the other hand, we show a large number of reports of alterations in the dopaminergic system after a TBI in animal models, in which modifications in the levels of DA, DAT, and HVA have been reported, as well as alterations in the expression of tyrosine hydroxylase (TH). We also describe the biological pathways, neuronal circuits, and molecular mechanisms potentially involved in mood and anxiety disorders that occur after TBI and are associated with alterations of the dopaminergic system in clinical studies and animal models. We describe the changes that occur in the clinical picture of post-TBI patients, such as alterations in mood and anxiety associated with DAT activity in the striatum, the relationship between post-TBI major depressive disorders (MDD) with lower availability of the DA receptors D2R and D3R in the caudate and thalamus, as well as a decrease in the volume of the substantia nigra (SN) associated with anxiety symptoms. With these findings, we discuss the possible relationship between the disorders caused by alterations in the dopaminergic system in patients with TBI.

The impact of the mesoprefrontal dopaminergic system on the maturation of interneurons in the murine prefrontal cortex.

The prefrontal cortex (PFC) undergoes a protracted maturation process. This is true both for local interneurons and for innervation from midbrain dopaminergic (mDA) neurons. In the striatum, dopaminergic (DA) neurotransmission is required for the maturation of medium spiny neurons during a critical developmental period. To investigate whether DA innervation influences the maturation of interneurons in the PFC, we used a conditional knockout (cKO) mouse model in which innervation from mDA neurons to the mPFC (mesoprefrontal innnervation) is not established during development. In this mouse model, the maturation of parvalbumin (PV) and calbindin (CB) interneuron populations in the PFC is dysregulated during a critical period in adolescence with changes persisting into adulthood. PV interneurons are particularly vulnerable to lack of mesoprefrontal input, showing an inability to maintain adequate PV expression with a concomitant decrease in Gad1 expression levels. Interestingly, lack of mesoprefrontal innervation does not appear to induce compensatory changes such as upregulation of DA receptor expression in PFC neurons or increased innervation density of other neuromodulatory (serotonergic and noradrenergic) innervation. In conclusion, our study shows that adolescence is a sensitive period during which mesoprefrontal input plays a critical role in promoting the maturation of specific interneuron subgroups. The results of this study will help to understand how a dysregulated mesoprefrontal DA system contributes to the pathophysiology of neurodevelopmental disorders.

In vitro modeling of the human dopaminergic system using spatially arranged ventral midbrain–striatum–cortex assembloids

Ventral midbrain dopaminergic neurons project to the striatum as well as the cortex and are involved in movement control and reward-related cognition. In Parkinson’s disease, nigrostriatal midbrain dopaminergic neurons degenerate and cause typical Parkinson’s disease motor-related impairments, while the dysfunction of mesocorticolimbic midbrain dopaminergic neurons is implicated in addiction and neuropsychiatric disorders. Study of the development and selective neurodegeneration of the human dopaminergic system, however, has been limited due to the lack of an appropriate model and access to human material. Here, we have developed a human in vitro model that recapitulates key aspects of dopaminergic innervation of the striatum and cortex. These spatially arranged ventral midbrain–striatum–cortical organoids (MISCOs) can be used to study dopaminergic neuron maturation, innervation and function with implications for cell therapy and addiction research. We detail protocols for growing ventral midbrain, striatal and cortical organoids and describe how they fuse in a linear manner when placed in custom embedding molds. We report the formation of functional long-range dopaminergic connections to striatal and cortical tissues in MISCOs, and show that injected, ventral midbrain-patterned progenitors can mature and innervate the tissue. Using these assembloids, we examine dopaminergic circuit perturbations and show that chronic cocaine treatment causes long-lasting morphological, functional and transcriptional changes that persist upon drug withdrawal. Thus, our method opens new avenues to investigate human dopaminergic cell transplantation and circuitry reconstruction as well as the effect of drugs on the human dopaminergic system.

Dopaminergic innervation of the human striatum: A unique relationship to mosaic organization

Dopaminergic innervation of the human striatum: A unique relationship to mosaic organization

Nigrostriatal tau pathology in parkinsonism and Parkinson's disease.

While Parkinson's disease remains clinically defined by cardinal motor symptoms resulting from nigrostriatal degeneration, it is now appreciated that the disease commonly consists of multiple pathologies, but it is unclear where these co-pathologies occur early in disease and whether they are responsible for the nigrostriatal degeneration. For the past number of years, we have been studying a well-characterized cohort of subjects with motor impairment that we have termed mild motor deficits. Motor deficits were determined on a modified and validated Unified Parkinson's Disease Rating Scale III but were insufficient in degree to diagnose Parkinson's disease. However, in our past studies, cases in this cohort had a selection bias, as both a clinical syndrome in between no motor deficits and Parkinson's disease, plus nigral Lewy pathology as defined post-mortem, were required for inclusion. Therefore, in the current study, we only based inclusion on the presence of a clinical phenotype with mild motor impairment insufficient to diagnose Parkinson's disease. Then, we divided this group further based upon whether or not subjects had a synucleinopathy in the nigrostriatal system. Here we demonstrate that loss of nigral dopaminergic neurons, loss of putamenal dopaminergic innervation and loss of the tyrosine hydroxylase-phenotype in the substantia nigra and putamen occur equally in mild motor deficit groups with and without nigral alpha-synuclein aggregates. Indeed, the common feature of these two groups is that both have similar degrees of AT8 positive phosphorylated tau, a pathology not seen in the nigrostriatal system of age-matched controls. These findings were confirmed with early (tau Ser208 phosphorylation) and late (tau Ser396/Ser404 phosphorylation) tau markers. This suggests that the initiation of nigrostriatal dopaminergic neurodegeneration occurs independently of alpha-synuclein aggregation and can be tau mediated.

Evolutionary scaling and cognitive correlates of primate frontal cortex microstructure.

Investigating evolutionary changes in frontal cortex microstructure is crucial to understanding how modifications of neuron and axon distributions contribute to phylogenetic variation in cognition. In the present study, we characterized microstructural components of dorsolateral prefrontal cortex, orbitofrontal cortex, and primary motor cortex from 14 primate species using measurements of neuropil fraction and immunohistochemical markers for fast-spiking inhibitory interneurons, large pyramidal projection neuron subtypes, serotonergic innervation, and dopaminergic innervation. Results revealed that the rate of evolutionary change was similar across these microstructural variables, except for neuropil fraction, which evolves more slowly and displays the strongest correlation with brain size. We also found that neuropil fraction in orbitofrontal cortex layers V-VI was associated with cross-species variation in performance on experimental tasks that measure self-control. These findings provide insight into the evolutionary reorganization of the primate frontal cortex in relation to brain size scaling and its association with cognitive processes.

Neuromelanin accumulation drives endogenous synucleinopathy in non-human primates.

Although neuromelanin is a dark pigment characteristic of dopaminergic neurons in the human substantia nigra pars compacta, its potential role in the pathogenesis of Parkinson's disease (PD) has often been neglected since most commonly used laboratory animals lack neuromelanin. Here we took advantage of adeno-associated viral vectors encoding the human tyrosinase gene for triggering a time-dependent neuromelanin accumulation within substantia nigra pars compacta dopaminergic neurons in macaques up to similar levels of pigmentation as observed in elderly humans. Furthermore, neuromelanin accumulation induced an endogenous synucleinopathy mimicking intracellular inclusions typically observed in PD together with a progressive degeneration of neuromelanin-expressing dopaminergic neurons. Moreover, Lewy body-like intracellular inclusions were observed in cortical areas of the frontal lobe receiving dopaminergic innervation, supporting a circuit-specific anterograde spread of endogenous synucleinopathy by permissive trans-synaptic templating. In summary, the conducted strategy resulted in the development and characterization of a new macaque model of PD matching the known neuropathology of this disorder with unprecedented accuracy. Most importantly, evidence is provided showing that intracellular aggregation of endogenous α-synuclein is triggered by neuromelanin accumulation, therefore any therapeutic approach intended to decrease neuromelanin levels may provide appealing choices for the successful implementation of novel PD therapeutics.

Dense dopaminergic innervation of the peri-infarct cortex despite dopaminergic cell loss after a pure motor-cortical stroke in rats.

After ischemic stroke, the cortex directly adjacent to the ischemic core (i.e., the peri-infarct cortex, PIC) undergoes plastic changes that facilitate motor recovery. Dopaminergic signaling is thought to support this process. However, ischemic stroke also leads to the remote degeneration of dopaminergic midbrain neurons, possibly interfering with this beneficial effect. In this study, we assessed the reorganization of dopaminergic innervation of the PIC in a rat model of focal cortical stroke. Adult Sprague-Dawley rats either received a photothrombotic stroke (PTS) in the primary motor cortex (M1) or a sham operation. 30 days after PTS or sham procedure, the retrograde tracer Micro Ruby (MR) was injected into the PIC of stroke animals or into homotopic cortical areas of matched sham rats. Thus, dopaminergic midbrain neurons projecting into the PIC were identified based on MR signal and immunoreactivity against tyrosine hydroxylase (TH), a marker for dopaminergic neurons. The density of dopaminergic innervation within the PIC was assessed by quantification of dopaminergic boutons indicated by TH-immunoreactivity. Regarding postsynaptic processes, expression of dopamine receptors (D1- and D2) and a marker of the functional signal cascade (DARPP-32) were visualized histologically. Despite a 25% ipsilesional loss of dopaminergic midbrain neurons after PTS, the number and spatial distribution of dopaminergic neurons projecting to the PIC was not different compared to sham controls. Moreover, the density of dopaminergic innervation in the PIC was significantly higher than in homotopic cortical areas of the sham group. Within the PIC, D1-receptors were expressed in neurons, whereas D2-receptors were confined to astrocytes. The intensity of D1- and DARPP-32 expression appeared to be higher in the PIC compared to the contralesional homotopic cortex. Our data suggest a sprouting of dopaminergic fibers into the PIC and point to a role for dopaminergic signaling in reparative mechanisms post-stroke, potentially related to recovery.

Investigating the potential effects of α-synuclein aggregation on susceptibility to chronic stress in a mouse Parkinson’s disease model

BackgroundParkinson’s disease (PD) is a motor disorder characterized by the degeneration of dopaminergic neurons, putatively due to the accumulation of α-synuclein (α-syn) in Lewy bodies (LBs) in Substantia Nigra. PD is also associated with the formation of LBs in brain areas responsible for emotional and cognitive regulation such as the amygdala and prefrontal cortex, and concurrent depression prevalence in PD patients. The exact link between dopaminergic cell loss, α-syn aggregation, depression, and stress, a major depression risk factor, is unclear. Therefore, we aimed to explore the interplay between sensitivity to chronic stress and α-syn aggregation.MethodsBilateral injections of α-syn preformed fibrils (PFFs) into the striatum of C57Bl/6 J mice were used to induce α-syn aggregation. Three months after injections, animals were exposed to chronic social defeat stress.Resultsα-syn aggregation did not affect stress susceptibility but independently caused increased locomotor activity in the open field test, reduced anxiety in the light–dark box test, and increased active time in the tail suspension test. Ex vivo analysis revealed modest dopaminergic neuron loss in the substantia nigra and reduced dopaminergic innervation in the dorsal striatum in PFFs injected groups. α-Syn aggregates were prominent in the amygdala, prefrontal cortex, and substantia nigra, with minimal α-syn aggregation in the raphe nuclei and locus coeruleus.ConclusionsProgressive bilateral α-syn aggregation might lead to compensatory activity increase and alterations in emotionally regulated behavior, without affecting stress susceptibility. Understanding how α-syn aggregation and degeneration in specific brain structures contribute to depression and anxiety in PD patients requires further investigation.

Cellular, Behavioral, and Locomotor Effects of Oral Nicotine in Male Rats with Bilateral Lesions in the Ventrolateral Striatum Induced with 6-OHDA

Objective: Parkinson's disease is a progressive neurodegenerative disease having a spectrum of non-motor to motor symptoms. Unrelated to motor symptoms of sensory, autonomic, and neuropsychiatric symptoms often appear early in the course of the disease. It is a remarkable observation that patients in the premotor phase can easily quit smoking without help. This study was intended to investigate the interrelation between nicotine and the partial loss of dopaminergic innervation in the ventrolateral striatum induced by 6-OHDA. 
 Methods: We used an experimental premotor parkinsonism model. The oral nicotine preference of rats was investigated with the two-bottle free choice method. The behaviors related to locomotor activity and emotional state were evaluated with a locomotor activity test, elevated plus maze, and forced swimming test. Histopathological evaluation was performed in the striatum by staining techniques using hematoxylin+eosin (H&E) and immunohistochemistry markers (caspase-3, and MAP-2).
 Results: Bilateral 6-OHDA lesions did not lead to a significant alteration in the total locomotor activity or nicotine preference. Nicotine increased horizontal but decreased vertical movements in addition to increasing anxiolytic but also depressive effects in the OHDA lesion group. The number of apoptotic cells was significantly lower in the lesion group receiving nicotine compared to those not receiving nicotine.
 Conclusion: Our experimental study points to the role of oral nicotine in male rats with bilateral striatal 6-OHDA lesions in the ventrolateral striatum. Further studies are needed to understand the relationship between loss of dopaminergic innervation in the striatum and nicotine consumption.

Hedonic eating, obesity, and addiction result from increased neuropeptide Y in the nucleus accumbens during human brain evolution

The nucleus accumbens (NAc) is central to motivation and action, exhibiting one of the highest densities of neuropeptide Y (NPY) in the brain. Within the NAc, NPY plays a role in reward and is involved in emotional behavior and in increasing alcohol and drug addiction and fat intake. Here, we examined NPY innervation and neurons of the NAc in humans and other anthropoid primates in order to determine whether there are differences among these various species that would correspond to behavioral or life history variables. We quantified NPY-immunoreactive axons and neurons in the NAc of 13 primate species, including humans, great apes, and monkeys. Our data show that the human brain is unique among primates in having denser NPY innervation within the NAc, as measured by axon length density to neuron density, even after accounting for brain size. Combined with our previous finding of increased dopaminergic innervation in the same region, our results suggest that the neurochemical profile of the human NAc appears to have rendered our species uniquely susceptible to neurophysiological conditions such as addiction. The increase in NPY specific to the NAc may represent an adaptation that favors fat intake and contributes to an increased vulnerability to eating disorders, obesity, as well as alcohol and drug dependence. Along with our findings for dopamine, these deeply rooted structural attributes of the human brain are likely to have emerged early in the human clade, laying the groundwork for later brain expansion and the development of cognitive and behavioral specializations.

Anatomical characterisation of three different psychosurgical targets in the subthalamic area: from the basal ganglia to the limbic system.

Effective neural stimulation for the treatment of severe psychiatric disorders needs accurate characterisation of surgical targets. This is especially true for the medial subthalamic region (MSR) which contains three targets: the anteromedial STN for obsessive compulsive disorder (OCD), the medial forebrain bundle (MFB) for depression and OCD, and the "Sano triangle" for pathological aggressiveness. Blocks containing the subthalamic area were obtained from two human brains. After obtaining 11.7-Tesla MRI, blocks were cut in regular sections for immunohistochemistry. Fluorescent in situ hybridisation was performed on the macaque MSR. Electron microscopic observation for synaptic specialisation was performed on human and macaque subthalamic fresh samples. Images of human brain sections were reconstructed in a cryoblock which was registered on the MRI and histological slices were then registered. The STN contains glutamatergic and fewer GABAergic neurons and has no strict boundary with the adjacent MSR. The anteromedial STN has abundant dopaminergic and serotoninergic innervation with very sparse dopaminergic neurons. The MFB is composed of dense anterior dopaminergic and posterior serotoninergic fibres, and fewer cholinergic and glutamatergic fibres. Medially, the Sano triangle presumably contains orexinergic terminals from the hypothalamus, and neurons with strong nuclear oestrogen receptor-alpha staining with a decreased anteroposterior and mediolateral gradient of staining. These findings provide new insight regarding MSR cells and their fibre specialisation, forming a transition zone between the basal ganglia and the limbic systems. Our 3D reconstruction enabled us to visualize the main histological features of the three targets which should enable better targeting and understanding of neuromodulatory stimulation results in severe psychiatric conditions.

Longitudinal assessment of social cognition in de novo Parkinson’s disease patients and its relationship with dopaminergic innervation

BackgroundSocial Cognition (SC) has been scarcely studied in Parkinson’s disease (PD), and findings in early disease are controversial. SC encompasses different capacities such as facial emotion recognition (FER); Theory of Mind (ToM), the ability to understand other people’s intentions (cognitive-ToM) and emotions (affective-ToM); and self-monitoring, the ability to regulate one’s own behavior in social contexts. A relationship between dopaminergic deficit and SC in PD has been suggested. ObjectivesTo prospectively assess, over a two-year period, SC in newly diagnosed drug-naïve, cognitively normal and non-depressed PD patients. Furthermore, we aimed to evaluate the relationship between SC and Fluorodopa (Positron Emission Tomography) Ki uptake, which is a marker of dopaminergic depletion. MethodsWe compared SC performance between 25 de novo PD patients and 20 healthy controls (HC), and within-patients at baseline and two-year follow-up. The SC assessment included FER, ToM, as well as self-monitoring measures. The relationship between SC and dopaminergic innervation was also assessed in patients. ResultsSC scores did not differ between PD and HC groups at baseline, nor between baseline and follow-up evaluation in PD. A significant positive correlation between self-monitoring and Fluorodopa Ki uptake in the left pallidum in PD patients was found at baseline. At follow-up, ToM (stories) positively correlated with Fluorodopa Ki uptake in the right thalamus and the left putamen. ConclusionSC appears to be preserved in de novo PD and remains stable in the short-term. Although more evidence is needed, our results support a relationship between dopamine innervation in subcortical regions and SC.

Pioglitazone enhances brain mitochondrial biogenesis and phase II detoxification capacity in neonatal rats with 6-OHDA-induced unilateral striatal lesions.

The psychostimulant methylphenidate (MPH) is the first-line pharmacological treatment for attention-deficit/hyperactivity disorder (ADHD), but has numerous adverse side effects. The PPARγ receptor agonist pioglitazone (PIO) is known to improve mitochondrial bioenergetics and antioxidant capacity, both of which may be deficient in ADHD, suggesting utility as an adjunct therapy. Here, we assessed the effects of PIO on ADHD-like symptoms, mitochondrial biogenesis and antioxidant pathways in multiple brain regions of neonate rats with unilateral striatal lesions induced by 6-hydroxydopamine (6-OHDA) as an experimental ADHD model. Unilateral striatal injection of 6-OHDA reduced ipsilateral dopaminergic innervation by 33% and increased locomotor activity. This locomotor hyperactivity was not altered by PIO treatment for 14 days. However, PIO increased the expression of proteins contributing to mitochondrial biogenesis in the striatum, hippocampus, cerebellum and prefrontal cortex of 6-OHDA-lesioned rats. In addition, PIO treatment enhanced the expression of the phase II transcription factor Nrf2 in the striatum, prefrontal cortex and cerebellum. In contrast, no change in the antioxidant enzyme catalase was observed in any of the brain regions analyzed. Thus, PIO may improve mitochondrial biogenesis and phase 2 detoxification in the ADHD brain. Further studies are required to determine if different dose regimens can exert more comprehensive therapeutic effects against ADHD neuropathology and behavior.

Opposing Spatially Segregated Function of Endogenous GDNF-RET Signaling in Cocaine Addiction.

Cocaine addiction is a serious condition with potentially lethal complications and no current pharmacological approaches towards treatment. Perturbations of the mesolimbic dopamine system are crucial to the establishment of cocaine-induced conditioned place preference and reward. As a potent neurotrophic factor modulating the function of dopamine neurons, glial cell line-derived neurotrophic factor (GDNF) acting through its receptor RET on dopamine neurons may provide a novel therapeutic avenue towards psychostimulant addiction. However, current knowledge on endogenous GDNF and RET function after the onset of addiction is scarce. Here, we utilized a conditional knockout approach to reduce the expression of the GDNF receptor tyrosine kinase RET from dopamine neurons in the ventral tegmental area (VTA) after the onset of cocaine-induced conditioned place preference. Similarly, after establishing cocaine-induced conditioned place preference, we studied the effect of conditionally reducing GDNF in the ventral striatum nucleus accumbens (NAc), the target of mesolimbic dopaminergic innervation. We find that the reduction of RET within the VTA hastens cocaine-induced conditioned place preference extinction and reduces reinstatement, while the reduction of GDNF within the NAc does the opposite: prolongs cocaine-induced conditioned place preference and increases preference during reinstatement. In addition, the brain-derived neurotrophic factor (BDNF) was increased and key dopamine-related genes were reduced in the GDNF cKO mutant animals after cocaine administration. Thus, RET antagonism in the VTA coupled with intact or enhanced accumbal GDNF function may provide a new approach towards cocaine addiction treatment.

Amygdala circuit transitions supporting developmentally-appropriate social behavior

Social behaviors dynamically change throughout the lifespan alongside the maturation of neural circuits. The basolateral region of the amygdala (BLA), in particular, undergoes substantial maturational changes from birth throughout adolescence that are characterized by changes in excitation, inhibition, and dopaminergic modulation. In this review, we detail the trajectory through which BLA circuits mature and are influenced by dopaminergic systems to guide transitions in social behavior in infancy and adolescence using data from rodents. In early life, social behavior is oriented towards approaching the attachment figure, with minimal BLA involvement. Around weaning age, dopaminergic innervation of the BLA introduces avoidance of novel peers into rat pups’ behavioral repertoire. In adolescence, social behavior transitions towards peer-peer interactions with a high incidence of social play-related behaviors. This transition coincides with an increasing role of the BLA in the regulation of social behavior. Adolescent BLA maturation can be characterized by an increasing integration and function of local inhibitory GABAergic circuits and their engagement by the medial prefrontal cortex (mPFC). Manipulation of these transitions using viral circuit dissection techniques and early adversity paradigms reveals the sensitivity of this system and its role in producing age-appropriate social behavior.