| 1. |
- Bimpisidis, Zisis, et al.
(author)
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The NeuroD6 Subtype of VTA Neurons Contributes to Psychostimulant Sensitization and Behavioral Reinforcement
- 2019
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In: eNeuro. - : SOC NEUROSCIENCE. - 2373-2822. ; 6:3
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Journal article (peer-reviewed)abstract
- Reward-related behavior is complex and its dysfunction correlated with neuropsychiatric illness. Dopamine (DA) neurons of the ventral tegmental area (VTA) have long been associated with different aspects of reward function, but it remains to be disentangled how distinct VTA DA neurons contribute to the full range of behaviors ascribed to the VTA. Here, a recently identified subtype of VTA neurons molecularly defined by NeuroD6 (NEX1M) was addressed. Among all VTA DA neurons, less than 15% were identified as positive for NeuroD6. In addition to dopaminergic markers, sparse NeuroD6 neurons expressed the vesicular glutamate transporter 2 (Vglut2) gene. To achieve manipulation of NeuroD6 VTA neurons, NeuroD6(NEX)-Cre-driven mouse genetics and optogenetics were implemented. First, expression of vesicular monoamine transporter 2 (VMAT2) was ablated to disrupt dopaminergic function in NeuroD6 VTA neurons. Comparing Vmat2(Cre)(lox/lox;NEX-) conditional knock-out (cKO) mice with littermate controls, it was evident that baseline locomotion, preference for sugar and ethanol, and place preference upon amphetamine-induced and cocaine-induced conditioning were similar between genotypes. However, locomotion upon repeated psychostimulant administration was significantly elevated above control levels in cKO mice. Second, optogenetic activation of NEX-Cre VTA neurons was shown to induce DA release and glutamatergic postsynaptic currents within the nucleus accumbens. Third, optogenetic stimulation of NEX-Cre VTA neurons in vivo induced significant place preference behavior, while stimulation of VTA neurons defined by Calretinin failed to cause a similar response. The results show that NeuroD6 VTA neurons exert distinct regulation over specific aspects of reward-related behavior, findings that contribute to the current understanding of VTA neurocircuitry.
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| 2. |
- Dorst, Matthijs C., et al.
(author)
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Polysynaptic inhibition between striatal cholinergic interneurons shapes their network activity patterns in a dopamine-dependent manner
- 2020
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Journal article (peer-reviewed)abstract
- Striatal activity is dynamically modulated by acetylcholine and dopamine, both of which are essential for basal ganglia function. Synchronized pauses in the activity of striatal cholinergic interneurons (ChINs) are correlated with elevated activity of midbrain dopaminergic neurons, whereas synchronous firing of ChINs induces local release of dopamine. The mechanisms underlying ChIN synchronization and its interplay with dopamine release are not fully understood. Here we show that polysynaptic inhibition between ChINs is a robust network motif and instrumental in shaping the network activity of ChINs. Action potentials in ChINs evoke large inhibitory responses in multiple neighboring ChINs, strong enough to suppress their tonic activity. Using a combination of optogenetics and chemogenetics we show the involvement of striatal tyrosine hydroxylase-expressing interneurons in mediating this inhibition. Inhibition between ChINs is attenuated by dopaminergic midbrain afferents acting presynaptically on D2 receptors. Our results present a novel form of interaction between striatal dopamine and acetylcholine dynamics.
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| 3. |
- Stagkourakis, Stefanos, et al.
(author)
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A Neuro-hormonal Circuit for Paternal Behavior Controlled by a Hypothalamic Network Oscillation
- 2020
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In: Cell. - : Elsevier BV. - 0092-8674 .- 1097-4172. ; 182:4, s. 960-975
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Journal article (peer-reviewed)abstract
- Parental behavior is pervasive throughout the animal kingdom and essential for species survival. However, the relative contribution of the father to offspring care differs markedly across animals, even between related species. The mechanisms that organize and control paternal behavior remain poorly understood. Using Sprague-Dawley rats and C57BL/6 mice, two species at opposite ends of the paternal spectrum, we identified that distinct electrical oscillation patterns in neuroendocrine dopamine neurons link to a chain of low dopamine release, high circulating prolactin, prolactin receptor-dependent activation of medial preoptic area galanin neurons, and paternal care behavior in male mice. In rats, the same parameters exhibit inverse profiles. Optogenetic manipulation of these rhythms in mice dramatically shifted serum prolactin and paternal behavior, whereas injecting prolactin into non-paternal rat sires triggered expression of parental care. These findings identify a frequency-tuned brain-endocrine-brain circuit that can act as a gain control system determining a species' parental strategy.
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| 4. |
- Stagkourakis, Stefanos, et al.
(author)
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Dopamine Release Dynamics in the Tuberoinfundibular Dopamine System
- 2019
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In: Journal of Neuroscience. - 0270-6474 .- 1529-2401. ; 39:21, s. 4009-4022
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Journal article (peer-reviewed)abstract
- The relationship between neuronal impulse activity and neurotransmitter release remains elusive. This issue is especially poorly understood in the neuroendocrine system, with its particular demands on periodically voluminous release of neurohormones at the interface of axon terminals and vasculature. Ashortage of techniques with sufficient temporal resolution has hindered real-time monitoring of the secretion of the peptides that dominate among the neurohormones. The lactotropic axis provides an important exception in neurochemical identity, however, as pituitary prolactin secretion is primarily under monoaminergic control, via tuberoinfundibular dopamine (TIDA) neurons projecting to the median eminence (ME). Here, we combined electrical or optogenetic stimulation and fast-scan cyclic voltammetry to address dopamine release dynamics in the male mouse TIDA system. Imposing different discharge frequencies during brief (3 s) stimulation of TIDA terminals in the ME revealed that dopamine output is maximal at 10 Hz, which was found to parallel the TIDA neuron action potential frequency distribution during phasic discharge. Over more sustained stimulation periods (150 s), maximal output occurred at 5 Hz, similar to the average action potential firing frequency of tonically active TIDA neurons. Application of the dopamine transporter blocker, methylphenidate, significantly increased dopamine levels in the ME, supporting a functional role of the transporter at the neurons' terminals. Lastly, TIDA neuron stimulation at the cell body yielded perisomatic release of dopamine, which may contribute to an ultrafast negative feedback mechanism to constrain TIDA electrical activity. Together, these data shed light on how spiking patterns in the neuroendocrine system translate to vesicular release toward the pituitary and identify how dopamine dynamics are controlled in the TIDA system at different cellular compartments.
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| 5. |
- Stagkourakis, Stefanos
(author)
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On innate behaviors : focus on parental behavior and aggression
- 2018
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Doctoral thesis (other academic/artistic)abstract
- The neural substrates orchestrating a number of social behaviors, including parental behavior and aggression, are known to exist in the hypothalamus. Through the control of the pituitary gland, the hypothalamus regulates the release of a number of hormones necessary for the physiological control of bodily functions and the expression of appropriate behaviors. In recent years the neuroscience community has invested large resources in identifying, through molecular markers, subsets of neurons whose activity impacts behavioral expression. This approach, however, has several weaknesses, among which is the assumption that a neuron’s function and output adhere to generalized principles. Consequently, such investigations often fail to identify the intricate organization of neural networks, which adapt the neural code in order to tune a system’s output to the behavior it modulates. The aim of this thesis is to expand on basic neurophysiological concepts regarding the complex organization within and among neural groups. Here we addressed the principles of how a set of neurons self-tune their activity through the use of their own neurotransmitter, intra- and inter-network connectivity designs and spike rate coding of neurotransmitter release. Following this interrogation of neural network properties, we attempted to link the activity of these neural nodes to behavioral output, where we identified two distinct subsets of neurons driving parental behavior and aggression respectively. In paper I, we performed a study on the properties of autoregulation in a neural network, and identified the ionic mechanisms through which the tuberoinfundibular dopamine (TIDA) neurons control their own activity via the use of their own neurotransmitter, dopamine (DA). In paper II, we encountered an unexpected species difference in baseline activity and oscillation frequency between rat and mouse TIDA neurons. Following an in-depth investigation, we attributed this difference to the presence vs complete absence of electrical coupling in the rat and mouse TIDA cells respectively. This generated the question of how different modes of TIDA neuron activity impact DA release at their terminals, which was addressed in paper III where, using fast-scan cyclic voltammetry, we performed the first investigation coupling patterns of electrophysiological activity to DA release in the TIDA system. In paper IV we addressed the possibility that this discrepancy in TIDA neuron activity has a behavioral impact. Following a step-by-step breakdown of the lactotropic axis in the male rat and mouse, we ultimately provided a link between TIDA neuron activity and the suppression vs expression of paternal behavior in the two species. The final part of this thesis includes two studies focusing on aggressive behavior. In paper V, we performed a functional interrogation of a subset of ventral premammillary (PMv) neurons involved in intermale aggression, while in paper VI we identified that the very same neurons are activated by maternal hormones and modulate the expression of maternal aggression in lactating female mice. Overall, the work presented in this thesis provides a step forward in our understanding of neural function and on the neural substrates underlying social behavior.
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