Cellular/Molecular
Dopamine Completes Midbrain Circuit with Negative Feedback
Cameron H. Good, Huikun Wang, Yuan-Hao Chen, Carlos A. Mejias-Aponte, Alexander F. Hoffman, et al.
(see pages 16853–16864)
The lateral habenula (LHb), a structure central to motivated behavior, makes excitatory connections with dopaminergic and non-dopaminergic neurons throughout the midbrain, including the ventral tegmental area (VTA). Recently LHb neurons were found to modulate VTA output indirectly via an inhibitory synapse with GABAergic neurons in the rostromedial tegmental nucleus (RMTg), or “tail” of the VTA. Now, Good et al. have elucidated a mysterious input from VTA neurons to the LHb that contributes to the circuit. They made whole-cell recordings alongside pharmacological manipulations of LHb neurons and found that dopamine elicited a depolarizing current in some cells; this depolarization required D4-type dopamine receptors as well as hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Synaptic glutamate release onto LHb neurons was also increased by dopamine. Retrograde labeling revealed that these effects occurred in LHb cells projecting to the RMTg, not to the VTA. The findings suggest that the VTA–LHb connection provides negative feedback—perhaps to dampen dopaminergic output after a period of activation.
Development/Plasticity/Repair
Gestational Inflammation Repatterns Cortex, Social Behavior
Pamela A. Carpentier, Ursula Haditsch, Amy E. Braun, Andrea V. Cantu, Hyang Mi Moon, et al.
(see pages 16874–16888)
Gestational maternal illness increases risk for autism spectrum disorder or schizophrenia. Early in fetal development, placental vulnerability—to maternal inflammatory molecules, in particular—coincides with cortical neurogenesis. Previous work has suggested that specific immune molecules cause placental dysfunction affecting neuronal precursor proliferation during a vulnerable period around embryonic day 12.5 (ED12.5). Carpentier et al. now build on that work. They gave pregnant mice a dose of lipopolysaccharide (LPS) at ED12.5, which caused fetal brain hypoxia followed by reduced progenitor cell proliferation. They next examined the brains of these pups and found that the number of ED12.5-born neurons was unchanged, but the neurons were abnormally distributed within the cortex, with an over-representation in outer compared to inner layers. The opposite pattern was detected in neurons born three days later at ED15.5. Sub-populations of projection and interneurons were differentially affected, changing the composition of the cortex. Initial experiments hinted that the repatterning affected social learning behaviors in adulthood.
Fetal hypoxia decreased the number of cortical cells entering the mitotic cycle both 2 h (white) and 24 h (red) later, and there was a corresponding increase in the fraction of cells that exited the cell cycle (green) between these time points. See the article by Carpentier et al. for details.
Systems/Circuits
Two Cortical Areas Oppositely Influence Dopaminergic Neurons
Mary H. Patton, Brandon T. Bizup, and Anthony A. Grace
(see pages 16865–16873)
The mesolimbic dopamine system plays an important role in goal-directed behavior and has been linked to mental illnesses, but its far-reaching connections throughout the brain remain incompletely understood. The medial prefrontal cortex (mPFC) exerts control over dopamine (DA) neurons in the ventral tegmental area (VTA) via connections from two distinct compartments: the infralimbic and prelimbic cortices (ilPFC and plPFC, respectively). Previous studies indicated these areas have opposite influences on behavior. Patton et al. made in vivo extracellular electrophysiological recordings from dopaminergic cells in the VTA of anesthetized rats. They measured the number of spontaneously active neurons as well as the basal firing rate and bursting activity. To manipulate the ilPFC and plPFC, the researchers infused the cortices either with NMDA to activate neurons or with tetrodotoxin to quell activity. VTA firing rate and bursting behaviors were unaffected by the manipulations, but the number of spontaneously active neurons was influenced in opposite directions by the two cortical areas. The basolateral amygdala and ventral hippocampus influenced the network as well.
Behavioral/Cognitive
Antidepressant Drug Effect Depends on Adrenoceptor Genotype
Ayana A. Gibbs, Carla E. Bautista, Florence D. Mowlem, Kris H. Naudts, and Theodora Duka
(see pages 17023–17028)
Emotional memory formation depends on signaling by the neurotransmitter noradrenaline. The ADRA2B gene encodes the alpha-2B adrenoceptor, which regulates norepinephrine release. A recent study linked a common mutation in ADRA2B to emotional memory in both healthy and traumatized populations. This week, Gibbs et al. connect that same ADRA2B variant in about 100 healthy male volunteers to their responses to emotional memory tests either with or without the antidepressant drug reboxetine, a noradrenaline reuptake inhibitor. Everyone forms stronger memories for negative than for neutral emotional stimuli, but this effect was enhanced in unmedicated carriers of the ADRA2B mutation. Participants given a dose of reboxetine saw less of that negative memory bias, as expected from the drug's mechanism of action—but only in subjects that did not carry the ADRA2B mutation. The report further clarifies how genotype information might be used to personalize treatments for mood disorders such as post-traumatic stress disorder.
