Murine arcuate nucleus kisspeptin neurons communicate with GnRH neurons in utero.

Puberty is a transition period of reproductive development from juvenile stages to adulthood and depends upon the activity of gonadotropin-releasing hormone (GnRH) neurons. GnRH neurons are initially activated in utero but remain quiescent throughout the juvenile period. Premature reactivation of GnRH neurons results in precocious puberty in mice and humans, but the mechanisms underlying developmental control of GnRH neuron activity remain unknown. The neuropeptide kisspeptin, a potent activator of GnRH neurons that is implicated as a critical permissive signal triggering puberty and a major regulator of the adult female hypothalamus-pituitary-gonadal axis, is paradoxically produced by neurons in the developing brain well before puberty onset. Thus, the neural circuits controlling the timing of reproductive maturation remain elusive. Here, we delineate the underlying neural circuitry using conditional genetic transsynaptic tracing in female mouse embryos. We find that kisspeptin-producing neurons in the arcuate nucleus (ARC) already communicate with a specific subset of GnRH neurons in utero. We show that ARC kisspeptin neurons are upstream of GnRH neurons, and that GnRH neuron connectivity to ARC kisspeptin neurons does not depend on their spatial position in the brain. Furthermore, we demonstrate that the neural circuits between ARC kisspeptin and GnRH neurons are fully established and operative before birth. Finally, we find that most GnRH neurons express the kisspeptin receptor GPR54 upon circuit formation, suggesting that the signaling system implicated in gatekeeping puberty becomes operative in the embryo.

Reorganization of adolescent prefrontal cortex circuitry is required for mouse cognitive maturation.

Most cognitive functions involving the prefrontal cortex emerge during late development. Increasing evidence links this delayed maturation to the protracted timeline of prefrontal development, which likely does not reach full maturity before the end of adolescence. However, the underlying mechanisms that drive the emergence and fine-tuning of cognitive abilities during adolescence, caused by circuit wiring, are still unknown. Here, we continuously monitored prefrontal activity throughout the postnatal development of mice and showed that an initial activity increase was interrupted by an extensive microglia-mediated breakdown of activity, followed by the rewiring of circuit elements to achieve adult-like patterns and synchrony. Interfering with these processes during adolescence, but not adulthood, led to a long-lasting microglia-induced disruption of prefrontal activity and neuronal morphology and decreased cognitive abilities. These results identified a nonlinear reorganization of prefrontal circuits during adolescence and revealed its importance for adult network function and cognitive processing.

Finding the missing and unknown: Novel educational approaches to warming up cold cases.

In recent years, students in police academies and higher education institutions around the world have worked together to analyse cold cases including long-term missing persons cases in collaboration with investigators and prosecutors. In 2020, three European organisations, the Police Expert Network on Missing Persons (PEN-MP), AMBER Alert Europe and Locate International, succeeded in connecting these educational organisations enabling them to work collectively on cases and conduct cold case analyses (CCA) across international borders. The International Cold Case Analysis Project (ICCAP) learning objectives were to 1) collect the necessary information about the victim, 2) reconstruct the crime, and 3) investigate trace control. In a learning objective-based evaluation using Computer-Assisted Web Interviewing, 76 participating students from the German and International ICCAP teams were asked to complete a pre- and post-review questionnaire to self-assess their personal competence development. Participants reported significant increases in competence in all evaluated areas, thus demonstrating that authentic and relevant collaborations can enrich the learning environment, promote the use of professional skills, and provide significant knowledge exchange opportunities between academia and industry. Drawing on case studies of cold case missing persons' investigations and unidentified found remains, this article shares how university academics, students and community volunteers can work together nationally and internationally to find out what has happened to missing people and how we can more effectively identify the previously unidentified. In so doing, we share the expertise required to progress these cold cases and provide recommendations to support other institutions and organisations in adopting this innovative approach.

A transient developmental increase in prefrontal activity alters network maturation and causes cognitive dysfunction in adult mice.

Disturbed neuronal activity in neuropsychiatric pathologies emerges during development and might cause multifold neuronal dysfunction by interfering with apoptosis, dendritic growth, and synapse formation. However, how altered electrical activity early in life affects neuronal function and behavior in adults is unknown. Here, we address this question by transiently increasing the coordinated activity of layer 2/3 pyramidal neurons in the medial prefrontal cortex of neonatal mice and monitoring long-term functional and behavioral consequences. We show that increased activity during early development causes premature maturation of pyramidal neurons and affects interneuronal density. Consequently, altered inhibitory feedback by fast-spiking interneurons and excitation/inhibition imbalance in prefrontal circuits of young adults result in weaker evoked synchronization of gamma frequency. These structural and functional changes ultimately lead to poorer mnemonic and social abilities. Thus, prefrontal activity during early development actively controls the cognitive performance of adults and might be critical for cognitive symptoms in neuropsychiatric diseases.

Multisensory integration in rodent tactile but not visual thalamus.

Behavioural performance requires a coherent perception of environmental features that address multiple senses. These diverse sensory inputs are integrated in primary sensory cortices, yet it is still largely unknown whether their convergence occurs even earlier along the sensory tract. Here we investigate the role of putatively modality-specific first-order (FO) thalamic nuclei (ventral posteromedial nucleus (VPM), dorsal lateral geniculate nucleus (dLGN)) and their interactions with primary sensory cortices (S1, V1) for multisensory integration in pigmented rats in vivo. We show that bimodal stimulation (i.e. simultaneous light flash and whisker deflection) enhances sensory evoked activity in VPM, but not dLGN. Moreover, cross-modal stimuli reset the phase of thalamic network oscillations and strengthen the coupling efficiency between VPM and S1, but not between dLGN and V1. Finally, the information flow from VPM to S1 is enhanced. Thus, FO tactile, but not visual, thalamus processes and relays sensory inputs from multiple senses, revealing a functional difference between sensory thalamic nuclei during multisensory integration.

Immunomodulatory effect of plasmids co-expressing cytokines in classical swine fever virus subunit gp55/E2-DNA vaccination.

The aim of this study was to determine the immunomodulatory effects of IL-12, IL-18 and CD154 (CD40 ligand, CD40L) in DNA-vaccination against the classical swine fever virus. Four recombinant plasmids were constructed including the CSFV coding region for the glycoprotein gp55/E2 alone or together with porcine IL-12, IL-18 or CD154 genes. Five groups of four pigs each were immunized intramuscularly (i.m.) three times with the respective constructs. The control group was inoculated with empty plasmid DNA. Eighteen days after the final immunization, the pigs were challenged with a lethal dose of CSFV strain Eystrup and monitored for a further 16 days. This study showed that co-delivery of IL-18 and CD154 induced an earlier appearance of serum antibodies, reduced B-cell deficiency after infection and protected pigs against a lethal CSFV infection. In contrast, co-delivery of IL-12 led to a reduced titer of neutralizing antibodies and protection against a lethal CSFV challenge in comparison to the other pigs and to pigs that were immunized with a gp55/E2 plasmid alone.