The evolutionarily conserved peripheral benzodiazepine receptor (PBR), or 18-kDa translocator protein (TSPO), is thought to be essential for cholesterol transport and steroidogenesis, and thus life. TSPO has been proposed as a biomarker of neuroinflammation and a new drug target in neurological diseases ranging from Alzheimer’s disease to anxiety. Here we show that global C57BL/6-Tspotm1GuWu(GuwiyangWurra)-knockout mice are viable with normal growth, lifespan, cholesterol transport, blood pregnenolone concentration, protoporphyrin IX metabolism, fertility and behaviour. However, while the activation of microglia after neuronal injury appears to be unimpaired, microglia from GuwiyangWurraTSPO knockouts produce significantly less ATP, suggesting reduced metabolic activity. Using the isoquinoline PK11195, the ligand originally used for the pharmacological and structural characterization of the PBR/TSPO, and the imidazopyridines CLINDE and PBR111, we demonstrate the utility of GuwiyangWurraTSPO knockouts to provide robust data on drug specificity and selectivity, both in vitro and in vivo, as well as the mechanism of action of putative TSPO-targeting drugs.

The acquisition of new goal-directed actions requires the encoding of action-outcome associations. At a neural level, this encoding has been hypothesized to involve a prefronto-striatal circuit extending between the prelimbic cortex (PL) and the posterior dorsomedial striatum (pDMS); however, no research identifying this pathway with any precision has been reported. We started by mapping the prelimbic input to the dorsal and ventral striatum using a combination of retrograde and anterograde tracing with CLARITY and established that PL-pDMS projections share some overlap with projections to the nucleus accumbens core (NAc) in rats. We then tested whether each of these pathways were functionally required for goal-directed learning; we used a pathway-specific dual-virus chemogenetic approach to selectively silence pDMS-projecting or NAc-projecting PL neurons during instrumental training and tested rats for goal-directed action. We found that silencing PL-pDMS projections abolished goal-directed learning, whereas silencing PL-NAc projections left goal-directed learning intact. Finally, we used a three-virus approach to silence bilateral and contralateral pDMS-projecting PL neurons and again blocked goal-directed learning. These results establish that the acquisition of new goal-directed actions depends on the bilateral PL-pDMS pathway driven by intratelencephalic cortical neurons.

The transcriptional repressor Snail2 is overexpressed in head and neck squamous cell carcinomas (HNSCC) relative to nonmalignant head and neck mucosal epithelium, and in locally recurrent relative to nonrecurrent HNSCCs. We investigated the mechanisms by which Snails might contribute to the pathogenesis of HNSCCs using cell biological and molecular analyses. Oral keratinocytes that expressed Snails acquired an enhanced ability to attract monocytes and to invade a dense interstitial collagen matrix. They were also found to up-regulate production of proinflammatory cytokines and cyclooxygenase-2 (COX2), which have previously been shown to correlate with malignancy. Induction of nuclear factor-KB transcriptional activity by Snails was weak and not sufficient to account for the elevated levels of COX2, interleukin (IL)-6, IL8, or CXCL1. In addition, expression of Snails in oral keratinocytes impaired desquamation in vitro and strongly repressed expression of both ELF3 and matriptase-1, which play important roles in the terminal differentiation of keratinocytes. Reexpression of matriptase-1 in Snail-expressing cells partially rescued desquamation. This implicates Snails as contributing to malignancy both at the early stages, by impeding terminal differentiation, and at later stages, when invasion and inflammation are important.

Cofilin rods and aggregates signify events initiated early in the pathological cascade. Further definition of the mechanisms leading to their formation in the human brain will provide insights into the cellular causes of AD.