Characterization of transgenic mouse models targeting neuromodulatory systems reveals organizational principles of the dorsal raphe.
2019; 10 (1): 4633
The dorsal raphe (DR) is a heterogeneous nucleus containing dopamine (DA), serotonin (5HT), ?-aminobutyric acid (GABA) and glutamate neurons. Consequently, investigations of DR circuitry require Cre-driver lines that restrict transgene expression to precisely defined cell populations. Here, we present a systematic evaluation of mouse lines targeting neuromodulatory cells in the DR. We find substantial differences in specificity between lines targeting DA neurons, and in penetrance between lines targeting 5HT neurons. Using these tools to map DR circuits, we show that populations of neurochemically distinct DR neurons are arranged in a stereotyped topographical pattern, send divergent projections to amygdala subnuclei, and differ in their presynaptic inputs. Importantly, targeting DR DA neurons using different mouse lines yielded both structural and functional differences in the neural circuits accessed. These results provide a refined model of DR organization and support a comparative, case-by-case evaluation of the suitability of transgenic tools for any experimental application.
View details for DOI 10.1038/s41467-019-12392-2
View details for PubMedID 31604921
- A New Look at the Role of Mesoamygdaloid Dopamine Neurons in Aversive Conditioning. The Journal of neuroscience : the official journal of the Society for Neuroscience 2020; 40 (40): 7590?92
- Hot topic in optogenetics: new implications of in vivo tissue heating. Nature neuroscience 2019
Distinct neural mechanisms for the prosocial and rewarding properties of MDMA.
Science translational medicine
2019; 11 (522)
The extensively abused recreational drug (±)3,4-methylenedioxymethamphetamine (MDMA) has shown promise as an adjunct to psychotherapy for treatment-resistant psychiatric disease. It is unknown, however, whether the mechanisms underlying its prosocial therapeutic effects and abuse potential are distinct. We modeled both the prosocial and nonsocial drug reward of MDMA in mice and investigated the mechanism of these processes using brain region-specific pharmacology, transgenic manipulations, electrophysiology, and in vivo calcium imaging. We demonstrate in mice that MDMA acting at the serotonin transporter within the nucleus accumbens is necessary and sufficient for MDMA's prosocial effect. MDMA's acute rewarding properties, in contrast, require dopaminergic signaling. MDMA's prosocial effect requires 5-HT1b receptor activation and is mimicked by d-fenfluramine, a selective serotonin-releasing compound. By dissociating the mechanisms of MDMA's prosocial effects from its addictive properties, we provide evidence for a conserved neuronal pathway, which can be leveraged to develop novel therapeutics with limited abuse liability.
View details for DOI 10.1126/scitranslmed.aaw6435
View details for PubMedID 31826983
Viral vector strategies for investigating midbrain dopamine circuits underlying motivated behaviors.
Pharmacology, biochemistry, and behavior
2018; 174: 23?32
Midbrain dopamine (DA) neurons have received significant attention in brain research because of their central role in reward processing and their dysfunction in neuropsychiatric disorders such as Parkinson's disease, drug addiction, depression and schizophrenia. Until recently, it has been thought that DA neurons form a homogeneous population whose primary function is the computation of reward prediction errors. However, through the implementation of viral vector strategies, an unexpected complexity and diversity has been revealed at the anatomical, molecular and functional level. In this review, we discuss recent viral vector approaches that have been leveraged to dissect how different circuits involving distinct DA neuron subpopulations may contribute to the role of DA in reward- and aversion-related behaviors. We focus on studies that have used cell type- and projection-specific optogenetic manipulations, discuss the strengths and limitations of each approach, and critically examine emergent organizational principles that have led to a reclassification of midbrain DA neurons.
View details for DOI 10.1016/j.pbb.2017.02.006
View details for PubMedID 28257849