A Paleocortico-Thalamo-Cortical Circuit Operating Giant Synapses

The thalamus is a critical relay station in the pathway for sensory information to the cortex and additionally important for the intercortical information transfer. An exception is the olfactory system, as it does not require a thalamic relay step before the information reaches the cortex. Olfactory receptor neurons send axonal projections to the olfactory bulb, from where the information proceeds to the primary olfactory cortex. It is only from the piriform cortex (PIR) that the information is passed to the prefrontal cortex via direct projections and via the mediodorsal thalamus (MD). Aside the for a sensory system exceptional connectivity, does this circuit also stand out against other cortico-thalamo-cortical loops. The PIR belongs to the paleocortex instead of neocortex, the contributor to most other cortico-thalamo-cortical loops. This situation raises the question if paleocorticothalamic projections have the same function as their subcorticothalamic or neocorticothalamic equivalents? In this thesis, I utilize a highly precise spatiotemporal gene transfer system via adeno-associated viruses to label PIR synapses. In acute slice preparations these synapses may be excited individually by juxtapositioned near field simulation electrodes. Based on the kinetics of the evoked postsynaptic currents and immunohistological stainings, I propose glutamate as the principle neurotransmitter. The PIR-MD synapse displays short-term depression, as it has been shown for other thalamic afferences, classified as “drivers”. In an electronmicroscopic preparation the complex dendritic interface of PIR-MD synapses becomes apparent. Often multiple dendritic excrescences invade the presynaptic profile. The presynaptic lumen is filled with vesicles and mitochondria. Altogether the morphology is that of a typical driver synapse in the thalamus. Surprisingly, I found chemical synapses onto intermediate stretches of labeled axons, a constellation that has not been described in MD or elsewhere previously. In summary, the results show that the olfactory brain circuit may have an additional level of complexity, imposed by axo-axonal contacts, and that PIR-MD synapses function like driver synapses in other transthalamic projections. However, as the term “driver” suggests that it always evokes postsynaptic action potentials, which is not true for the PIR-MD synapse, the recently proposed term “class I” synapse is adopted

Mitochondria-Endoplasmic Reticulum Contacts in Reactive Astrocytes Promote Vascular Remodeling

Astrocytes have emerged for playing important roles in brain tissue repair; however, the underlying mechanisms remain poorly understood. We show that acute injury and blood-brain barrier disruption trigger the formation of a prominent mitochondrial-enriched compartment in astrocytic endfeet, which enables vascular remodeling. Integrated imaging approaches revealed that this mitochondrial clustering is part of an adaptive response regulated by fusion dynamics. Astrocyte-specific conditional deletion of Mitofusin 2 (Mfn2) suppressed perivascular mitochondrial clustering and disrupted mitochondria-endoplasmic reticulum (ER) contact sites. Functionally, two-photon imaging experiments showed that these structural changes were mirrored by impaired mitochondrial Ca2+ uptake leading to abnormal cytosolic transients within endfeet in vivo. At the tissue level, a compromised vascular complexity in the lesioned area was restored by boosting mitochondrial-ER perivascular tethering in MFN2-deficient astrocytes. These data unmask a crucial role for mitochondrial dynamics in coordinating astrocytic local domains and have important implications for repairing the injured brain

High density and ligand affinity confer ultrasensitive signal detection by a guanylyl cyclase chemoreceptor

Guanylyl cyclases (GCs), which synthesize the messenger cyclic guanosine 3′,5′-monophosphate, control several sensory functions, such as phototransduction, chemosensation, and thermosensation, in many species from worms to mammals. The GC chemoreceptor in sea urchin sperm can decode chemoattractant concentrations with single-molecule sensitivity. The molecular and cellular underpinnings of such ultrasensitivity are not known for any eukaryotic chemoreceptor. In this paper, we show that an exquisitely high density of 3 × 105 GC chemoreceptors and subnanomolar ligand affinity provide a high ligand-capture efficacy and render sperm perfect absorbers. The GC activity is terminated within 150 ms by dephosphorylation steps of the receptor, which provides a means for precise control of the GC lifetime and which reduces “molecule noise.” Compared with other ultrasensitive sensory systems, the 10-fold signal amplification by the GC receptor is surprisingly low. The hallmarks of this signaling mechanism provide a blueprint for chemical sensing in small compartments, such as olfactory cilia, insect antennae, or even synaptic boutons

A pathway from midcingulate cortex to posterior insula gates nociceptive hypersensitivity

The identity of cortical circuits mediating nociception and pain is largely unclear. The cingulate cortex is consistently activated during pain, but the functional specificity of cingulate divisions, the roles at distinct temporal phases of central plasticity and the underlying circuitry are unknown. Here we show in mice that the midcingulate division of the cingulate cortex (MCC) does not mediate acute pain sensation and pain affect, but gates sensory hypersensitivity by acting in a wide cortical and subcortical network. Within this complex network, we identified an afferent MCC-posterior insula pathway that can induce and maintain nociceptive hypersensitivity in the absence of conditioned peripheral noxious drive. This facilitation of nociception is brought about by recruitment of descendingserotonergic facilitatory projections to the spinal cord. These results have implications for our understanding of neuronal mechanisms facilitating the transition from acute to long-lasting pain