Scientific Understanding of Consciousness
Neurotransmitter Switching Regulates Behavior
Science 26 April 2013: Vol. 340 no. 6131 pp. 449-453
Neurotransmitter Switching in the Adult Brain Regulates Behavior
Davide Dulcis, Pouya Jamshidi, Stefan Leutgeb, Nicholas C. Spitzer
Neurobiology Section, Division of Biological Sciences and Center for Neural Circuits and Behavior, University of California, San Diego, La Jolla, CA 92093–0357, USA.
Kavli Institute for Brain and Mind, University of California, San Diego, La Jolla, CA 92093–0357, USA.
Neurotransmitters have been thought to be fixed throughout life, but whether sensory stimuli alter behaviorally relevant transmitter expression in the mature brain is unknown. We found that populations of interneurons in the adult rat hypothalamus switched between dopamine and somatostatin expression in response to exposure to short- and long-day photoperiods. Changes in postsynaptic dopamine receptor expression matched changes in presynaptic dopamine, whereas somatostatin receptor expression remained constant. Pharmacological blockade or ablation of these dopaminergic neurons led to anxious and depressed behavior, phenocopying performance after exposure to the long-day photoperiod. Induction of newly dopaminergic neurons through exposure to the short-day photoperiod rescued the behavioral consequences of lesions. Natural stimulation of other sensory modalities may cause changes in transmitter expression that regulate different behaviors.
Signal transmission in neuronal circuits uses specific neurotransmitters that bind to cognate receptors on other neurons. Genetic programs establish initial expression patterns of neurotransmitters in different classes of neurons, and activity-dependent neurotransmitter respecification modifies them during development, either adding or switching transmitters. It is unknown, however, whether sensory stimuli promote transmitter switching in addition to other neuroplastic changes in the adult brain. Alterations in photoperiod, circadian rhythm, and light exposure can each cause anxiogenic and depressive behavior in diurnal adult mammals. We hypothesized that nocturnal mammals would respond to light manipulation in the opposite manner and that these changes in behavior would be mediated by transmitter switching.
Our results demonstrate transmitter switching between dopamine and somatostatin in neurons in the adult rat brain, induced by exposure to short- and long-day photoperiods that mimic seasonal changes at high latitudes. The shifts in SST/dopamine expression are regulated at the transcriptional level, are matched by parallel changes in postsynaptic D2R/SST2/4R expression, and have pronounced effects on behavior. SST-IR/TH-IR local interneurons synapse on CRF-releasing cells, providing a mechanism by which the brain of nocturnal rats generates a stress response to a long-day photoperiod, contributing to depression and serving as functional integrators at the interface of sensory and neuroendocrine responses.
SST/dopamine interchange illustrates neuroplasticity in self-balancing networks that tunes neural function and behavior to a dynamic environment. The molecular mechanism remains to be discovered, but AST-1 and Etv1 transcription factors bind to a specific dopamine motif in Caenorhabditis elegans and mouse to drive the expression of genes that encode components necessary for synthesis, packaging, and reuptake of dopamine. Activity-dependent transmitter switching may serve functions similar to homeostatic synaptic scaling, changes in ion channel expression, and neuropeptide remodeling of sensory networks and is an additional form of brain plasticity to add to modifications of synaptic strength, synapse number, and electrical excitability. Sensory stimulation driving transmitter switching in specific microcircuits affected in neurological or psychiatric disorders could contribute to noninvasive restoration of normal function in the mature nervous system.
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Science 26 April 2013: Vol. 340 no. 6131 pp. 436-437
Plasticity in the Neurotransmitter Repertoire
Biology Department and Volen Center, Brandeis University, Waltham, MA 02454, USA.
In the earliest days of neuroscience, it was thought that a neuron made and released only a single chemical, known as a neurotransmitter, to send a signal across a synapse to an adjacent neuron. At the same time, it was deeply mysterious why so many signaling molecules were used in nervous systems. Subsequently, it became clear that many, if not most, neurons (including those in mammals) make and release two or more neurotransmitters including small-molecules and neuropeptides. As the list of these potential cotransmitters and their receptors has increased, we are faced with understanding the functional relevance of this embarrassment of riches for neural circuits and behavior. Neurotransmitters and neuromodulators (substances often released with small-molecule neurotransmitters) can elicit a variety of different actions on their neuron targets, including directly opening ion channels or acting through signal transduction pathways to alter neuronal excitability or synaptic transmission. Thus, characterizing the mixture of cotransmitters released by a neuron is important for understanding how neuronal circuits operate. The mechanisms that change the profile of neurotransmitter release provide opportunities for plastic changes in circuit function, and consequently in organism behavior. Researchers Dulcis et al. report changes in the neurotransmitter profile of neurons that underlie photoperiod-triggered changes in animal behavior. The findings argue that neurotransmitter switching is a new mechanism for neuroplasticity in adult nervous systems.
Early studies using cultured developing neurons showed that individual neurons can switch their transmitter phenotype. For example, peripheral sympathetic neurons that normally release norepinephrine as their neurotransmitter can undergo a developmental switch to acetylcholine. A role for this switch was shown for sympathetic neurons innervating rat sweat glands. These neurons release acetylcholine when innervating sweat glands, whereas they secrete norepinephrine when innervating other organs, including the heart. Subsequent work has studied the molecular pathways underlying these developmental switches and has demonstrated activity-dependent transmitter plasticity in adult rodent brains. This type of regulation became even more intriguing when it was found that the production of new neurotransmitters by neurons can induce new behaviors such as pigmentation changes in amphibian larvae
The work by Dulcis et al. is remarkable in that it ties these well-characterized phenomena to plasticity in the mammalian response to the light-dark cycle. Specifically, the exposure of adult rats to light was altered by keeping the animals in photoperiod chambers for a week on either long-day (19 hours of light and 5 hours of dark) or short-day (5 hours of light and 19 hours of dark) cycles. The number of dopamine-releasing neurons in several hypothalamic nuclei (clusters of neurons) increased with short-day cycles and decreased with long-day cycles, whereas the inverse was seen with somatostatin. Dopamine is a neurotransmitter whose functions in the brain include modulating cognition, motivation, mood, memory, and learning; somatostatin is a peptide neuromodulator that is widely expressed in the nervous system and may be involved in the regulation of stress responses. The number of dopamine receptors on target neurons in the brain increased and decreased homeostatically, likely to ensure that the changes in the cotransmission of dopamine and somatostatin would result in functional outcomes. Strikingly, the animals' behavior was also modified with short-day cycles, as seen in two assays thought to indicate mood, anxiety, and depression. Changes in light-dark cycle have profound effects on human mood and behavior as well, contributing to a variety of disorders such as seasonal affective disorder. Thus, there is now a potential mechanistic link among mood, photoperiod, and neurotransmitter plasticity that mirrors associations observed in humans among seasonal affective disorder, photoperiod, and dopamine signaling.
Supporting this link are measurements of corticotropin-releasing factor (CRF) secretion by adult rat hypothalamic neurons in response to different photoperiods. Dulcis et al. noted that the change in the ratio of dopaminergic signaling to somatostatin signaling correlated with changes in the amount of CRF and corticosteroid in the plasma. CRF is released by neurons in the mammalian brain that are targets of dopamine and somatostatin. This triggers a cascade of events that raises the concentration of circulating corticosteroids. These steroids have a wide range of physiological effects and have been implicated in stress and depression. The findings suggest that the transmitter switch potentially couples photoperiod and mood regulation. The ability of neurons to switch their neurotransmitter repertoire has been known for 40 years; the study of Dulcis et al. demonstrates the use of this mechanism to control adult behavior in response to sensory variation.
Although the work by Dulcis et al. was carried out in nocturnal rodents for which long-day photoperiods are stressful, it is possible to imagine broader implications of this work for human behavior in which short-day photoperiods are stressful. Admittedly, the mechanistic details in humans may be different. Nonetheless, given the ubiquitous ability of neurons to release multiple neurotransmitters and the demonstrated capacity for plasticity, it is critical to consider the potential role of transmitter plasticity in understanding the human brain in health and disease.
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