Circadian neurons in the paraventricular nucleus entrain and sustain daily rhythms in glucocorticoids

Signals from the central circadian pacemaker, the suprachiasmatic nucleus (SCN), must be decoded to generate daily rhythms in hormone release. Here, we hypothesized that the SCN entrains rhythms in the paraventricular nucleus (PVN) to time the daily release of corticosterone. In vivo recording revealed a critical circuit from SCN vasoactive intestinal peptide (SCNVIP)-producing neurons to PVN corticotropin-releasing hormone (PVNCRH)-producing neurons. PVNCRH neurons peak in clock gene expression around midday and in calcium activity about three hours later. Loss of the clock gene Bmal1 in CRH neurons results in arrhythmic PVNCRH calcium activity and dramatically reduces the amplitude and precision of daily corticosterone release. SCNVIP activation reduces (and inactivation increases) corticosterone release and PVNCRH calcium activity, and daily SCNVIP activation entrains PVN clock gene rhythms by inhibiting PVNCRH neurons. We conclude that daily corticosterone release depends on coordinated clock gene and neuronal activity rhythms in both SCNVIP and PVNCRH neurons.

Complement-associated loss of CA2 inhibitory synapses in the demyelinated hippocampus impairs memory

The complement system is implicated in synapse loss in the MS hippocampus, but the functional consequences of synapse loss remain poorly understood. Here, in post-mortem MS hippocampi with demyelination we find that deposits of the complement component C1q are enriched in the CA2 subfield, are linked to loss of inhibitory synapses and are significantly higher in MS patients with cognitive impairments compared to those with preserved cognitive functions. Using the cuprizone mouse model of demyelination, we corroborated that C1q deposits are highest within the demyelinated dorsal hippocampal CA2 pyramidal layer and co-localized with inhibitory synapses engulfed by microglia/macrophages. In agreement with the loss of inhibitory perisomatic synapses, we found that Schaffer collateral feedforward inhibition but not excitation was impaired in CA2 pyramidal neurons and accompanied by intrinsic changes and a reduced spike output. Finally, consistent with excitability deficits, we show that cuprizone-treated mice exhibit impaired encoding of social memories. Together, our findings identify CA2 as a critical circuit in demyelinated intrahippocampal lesions and memory dysfunctions in MS.

Complement-associated loss of CA2 inhibitory synapses in the demyelinated hippocampus impairs memory

The complement system is implicated in synapse loss in the MS hippocampus, but the functional consequences of synapse loss remain poorly understood. Here, in post-mortem MS hippocampi with demyelination we find that deposits of the complement component C1q are enriched in the CA2 subfield, are linked to loss of inhibitory synapses and are significantly higher in MS patients with cognitive impairments compared to those with preserved cognitive functions. Using the cuprizone mouse model of demyelination, we corroborated that C1q deposits are highest within the demyelinated dorsal hippocampal CA2 pyramidal layer, and co-localized with inhibitory synapses engulfed by microglia/macrophages. In agreement with the loss of inhibitory perisomatic synapses, we further found that Schaffer collateral feedforward inhibition but not excitation was impaired in CA2 pyramidal neurons and accompanied by a reduced spike output. Ultimately, we show that these electrophysiological changes were associated with an impaired encoding of social memories. Together, our findings identify CA2 as a critical circuit in demyelinated intrahippocampal lesions and memory dysfunctions in MS.

Paradoxically sparse chemosensory tuning in broadly-integrating external granule cells in the mouse accessory olfactory bulb

The accessory olfactory bulb (AOB) is a critical circuit in the mouse accessory olfactory system (AOS), but AOB processing is poorly understood compared to the main olfactory bulb (MOB). We used 2-photon GCaMP6f Ca2+ imaging in an ex vivo preparation to study the chemosensory tuning of AOB external granule cells (EGCs), an interneuron population hypothesized to broadly integrate from mitral cells (MCs). We measured MC and EGC tuning to natural chemosignal blends and monomolecular ligands, finding that EGC tuning was far sparser than MC tuning. Simultaneous patch-clamp electrophysiology and Ca2+ imaging indicated that this was only partially explained by lower GCaMP6f-to-spiking ratios in EGCs compared to MCs. Ex vivo patch-clamp recordings revealed that EGC subthreshold responsivity was broad, but monomolecular ligand responses were insufficient to elicit spiking. These results indicate that EGC spiking is selectively engaged by chemosensory blends, suggesting different roles for EGCs than analogous interneurons in the MOB.

How to Become War Machine, Or … A Low Hacktivist (Un)Methodology in Pieces

In recent years, digital media and networks have been increasingly used to deploy dissent, opposition and resistance. More frequently, beyond traditional media as communicational tools, politically-oriented hacking subjectivities like ‘Anonymous’ employ media as weapons. However, a similar material deployment of media actions cannot be studied as a static, clearly definable ‘thing’ based on a representational order. These media actions, as well as their compositional relations, and the processes through which they are originated, are mostly ephemeral. Moreover, their deployment is always actualised in emergent and unstable contexts, within which the elements at stake – involving human and non-human components – are continuously in change, acting often beyond representation. For this reason, I suggest a ‘low hacktivist methodology in pieces’ as a theoretical and practical exercise of assemblage for recognising and dealing with similar criticalities without imposing any impossible objectivity. Inspired by Wark’s ‘low theory’ and Guattarian ecosophy, such a ‘scattered’ (un)methodology is conceived as a ‘method assemblage’ capable of activating, rather than framing, the virtual ‘lines of flight’ of the (problematised) objects of research. Within such assemblages, in fact, subject and object are critically put into question, allowing new methodological strategies to deal with hacktivist media actions. Becoming ‘war machine’ is a temporary and fragmented attempt to ‘machinise’ with the forces populating hacktivist media assemblages. Here, an ontological reframing is needed: a confrontation with humanist paradigms that enables, as a critical circuit, the blossoming of theory from the same actions at stake.