Efferent projections of Vglut2, Foxp2, and Pdyn parabrachial neurons in mice.

The parabrachial nucleus (PB) is a complex structure located at the junction of the midbrain and hindbrain. Its neurons have diverse genetic profiles and influence a variety of homeostatic functions. While its cytoarchitecture and overall efferent projections are known, we lack comprehensive information on the projection patterns of specific neuronal subtypes in the PB. In this study, we compared the projection patterns of glutamatergic neurons here with a subpopulation expressing the transcription factor Foxp2 and a further subpopulation expressing the neuropeptide Pdyn. To do this, we injected an AAV into the PB region to deliver a Cre-dependent anterograde tracer (synaptophysin-mCherry) in three different strains of Cre-driver mice. We then analyzed 147 neuroanatomical regions for labeled boutons in every brain (n = 11). Overall, glutamatergic neurons in the PB region project to a wide variety of sites in the cerebral cortex, basal forebrain, bed nucleus of the stria terminalis, amygdala, diencephalon, and brainstem. Foxp2 and Pdyn subpopulations project heavily to the hypothalamus, but not to the cortex, basal forebrain, or amygdala. Among the few differences between Foxp2 and Pdyn cases was a notable lack of Pdyn projections to the ventromedial hypothalamic nucleus. Our results indicate that genetic identity determines connectivity (and therefore, function), providing a framework for mapping all PB output projections based on the genetic identity of its neurons. Using genetic markers to systematically classify PB neurons and their efferent projections will enhance the translation of research findings from experimental animals to humans.

Loss of corticostriatal and thalamostriatal synaptic terminals precedes striatal projection neuron pathology in heterozygous Q140 Huntington's disease mice.

Motor slowing, forebrain white matter loss, and striatal shrinkage have been reported in premanifest Huntington's disease (HD) prior to overt striatal neuron loss. We carried out detailed LM and EM studies in a genetically precise HD mimic, heterozygous Q140 HD knock-in mice, to examine the possibility that loss of corticostriatal and thalamostriatal terminals prior to striatal neuron loss underlies these premanifest HD abnormalities. In our studies, we used VGLUT1 and VGLUT2 immunolabeling to detect corticostriatal and thalamostriatal (respectively) terminals in dorsolateral (motor) striatum over the first year of life, prior to striatal projection neuron pathology. VGLUT1+ axospinous corticostriatal terminals represented about 55% of all excitatory terminals in striatum, and VGLUT2+ axospinous thalamostriatal terminals represented about 35%, with VGLUT1+ and VGLUT2+ axodendritic terminals accounting for the remainder. In Q140 mice, a significant 40% shortfall in VGLUT2+ axodendritic thalamostriatal terminals and a 20% shortfall in axospinous thalamostriatal terminals were already observed at 1 month of age, but VGLUT1+ terminals were normal in abundance. The 20% deficiency in VGLUT2+ thalamostriatal axospinous terminals persisted at 4 and 12 months in Q140 mice, and an additional 30% loss of VGLUT1+ corticostriatal terminals was observed at 12 months. The early and persistent deficiency in thalamostriatal axospinous terminals in Q140 mice may reflect a development defect, and the impoverishment of this excitatory drive to striatum may help explain early motor defects in Q140 mice and in premanifest HD. The loss of corticostriatal terminals at 1 year in Q140 mice is consistent with prior evidence from other mouse models of corticostriatal disconnection early during progression, and can explain both the measurable bradykinesia and striatal white matter loss in late premanifest HD.

Rapid structural remodeling of thalamocortical synapses parallels experience-dependent functional plasticity in mouse primary visual cortex.

Monocular lid closure (MC) causes a profound shift in the ocular dominance (OD) of neurons in primary visual cortex (V1). Anatomical studies in both cat and mouse V1 suggest that large-scale structural rearrangements of eye-specific thalamocortical (TC) axons in response to MC occur much more slowly than the shift in OD. Consequently, there has been considerable debate as to whether the plasticity of TC synapses, which transmit competing visual information from each eye to V1, contributes to the early functional consequences of MC or is simply a feature of long-term deprivation. Here, we used quantitative immuno-electron microscopy to examine the possibility that alterations of TC synapses occur rapidly enough to impact OD after brief MC. The effect of short-term deprivation on TC synaptic structure was examined in male C57BL/6 mice that underwent 3 and 7 d of MC or monocular retinal inactivation (MI) with tetrodotoxin. The data show that 3 d of MC is sufficient to induce substantial remodeling of TC synapses. In contrast, 3 d of MI, which alters TC activity but does not shift OD, does not significantly affect the structure of TC synapses. Our results support the hypothesis that the rapid plasticity of TC synapses is a key step in the sequence of events that shift OD in visual cortex.

Glutamatergic phenotype of hypothalamic neurosecretory systems: a novel aspect of central neuroendocrine regulation.

While three decades ago, the co-existence of classical neurotransmitters and peptide neuromodulators in a single neuronal cell was considered to be rather exceptional, the phenomenon that neurons have a complex transmitter phenotype now appears to be the general rule. Parvicellular and magnocellular neurosecretory systems consist of neuronal cells which are specialized in secreting peptide neurohormones into the blood-stream to regulate hypophyseal functions. This mini-review, dedicated to the memory of Mariann Fodor, summarizes the current knowledge about the classical neurotransmitter content of different hypothalamic neurosecretory systems, with a special focus on the occurrence and putative functions of glutamate in parvicellular and magnocellular neurosecretory cells.

Transient synaptic zinc-positive thalamocortical terminals in the developing barrel cortex.

In rat barrel cortex, layer 4 has a transiently high density of zinc-positive terminations from postnatal day (P)9 to P12 [P.W. Land & L. Shamalla-Hannah (2002)J. Comp. Neurol., 447, 43-56]. These terminations have been proposed to originate from cortico-cortical connections, but their exact origin is unknown. To determine their sources, we injected sodium selenite into the barrel cortex of two adult rats and 32 pups, from P5 to P28. As predicted, abundant zinc-positive cortically projecting neurons were visible around the injection sites and in distant cortical areas. From P9 to P13, however, neurons retrogradely labeled by zinc selenite occurred in the thalamus, in topographically appropriate regions of the ventroposterior medial (VPM) and posterior nuclei (Po). Because there are no previous reports of zinc-positive sensory thalamocortical connections, we sought corroboration of this unexpected finding by electron microscopy. This revealed a subset of boutons in layers 4 and 1, positive for both zinc and vesicular glutamate transporter 2, a protein used by thalamocortical terminations. Finally, in an additional nine rats, we carried out in situ hybridization for zinc transporter 3 mRNA. Moderate signal was detected in VPM and Po at P10, but this disappeared by P28. In contrast, a strong signal was apparent in the anterodorsal nucleus, which projects to limbic areas, and this persisted at P28. The timing of the transient zinc-positive terminations in the sensory thalamus roughly coincides with the onset of exploratory and whisking behavior in the middle of the second postnatal week; and this suggests zinc is important for activity-related refinement of circuitry.