Prolactin action is necessary for parental behavior in male mice

Parental care is critical for successful reproduction in mammals. In comparison to maternal care, the neuroendocrine mechanisms supporting paternal care are less well-studied. Laboratory mice show a mating-induced suppression of infanticide (normally observed in virgins) and onset of paternal behavior. Using this model, we sought to investigate whether the hormone prolactin plays a role in paternal behavior, as it does for maternal behavior. First, using c-fos immunoreactivity in Prlr-IRES-Cre-tdtomato reporter mouse sires, we show that the circuitry activated during paternal interactions contains prolactin-responsive neurons, including the medial preoptic area, bed nucleus of the stria terminalis, and medial amygdala. To evaluate whether prolactin action is required for the establishment and display of paternal behavior, we conditionally deleted the prolactin receptor (Prlr) from 3 distinct cell types: glutamatergic, GABAergic, and CaMKIIα-expressing forebrain neurons. Prlr-deletion from CaMKIIα-expressing forebrain neurons, but not from glutamatergic or GABAergic cells, resulted in a profound effect on paternal behavior, as none of these males completed the pup retrieval task. Finally, although sires do not show an acute increase in circulating prolactin levels in response to pups, pharmacological blockade of prolactin-release at the time of pup exposure resulted in failure to retrieve pups, similar to when the Prlr was deleted from CaMKIIα neurons, with prolactin administration rescuing this behavior. Taken together, our data show that paternal behavior in sires is dependent on basal levels of circulating prolactin acting at the Prlr on CaMKIIα-expressing neurons. These new data in male mice demonstrate that prolactin has a similar action in both sexes to promote parental care.

Lack of APP and APLP2 in GABAergic Forebrain Neurons Impairs Synaptic Plasticity and Cognition

Amyloid-β precursor protein (APP) is central to the pathogenesis of Alzheimer’s disease, yet its physiological functions remain incompletely understood. Previous studies had indicated important synaptic functions of APP and the closely related homologue APLP2 in excitatory forebrain neurons for spine density, synaptic plasticity, and behavior. Here, we show that APP is also widely expressed in several interneuron subtypes, both in hippocampus and cortex. To address the functional role of APP in inhibitory neurons, we generated mice with a conditional APP/APLP2 double knockout (cDKO) in GABAergic forebrain neurons using DlxCre mice. These DlxCre cDKO mice exhibit cognitive deficits in hippocampus-dependent spatial learning and memory tasks, as well as impairments in species-typic nesting and burrowing behaviors. Deficits at the behavioral level were associated with altered neuronal morphology and synaptic plasticity Long-Term Potentiation (LTP). Impaired basal synaptic transmission at the Schafer collateral/CA1 pathway, which was associated with altered compound excitatory/inhibitory synaptic currents and reduced action potential firing of CA1 pyramidal cells, points to a disrupted excitation/inhibition balance in DlxCre cDKOs. Together, these impairments may lead to hippocampal dysfunction. Collectively, our data reveal a crucial role of APP family proteins in inhibitory interneurons to maintain functional network activity.

Impact of Targeted Deletion of the Circadian Clock Gene Bmal1 in Excitatory Forebrain Neurons on Adult Neurogenesis and Olfactory Function

The circadian system is an endogenous timekeeping system that synchronizes physiology and behavior with the 24 h solar day. Mice with total deletion of the core circadian clock gene Bmal1 show circadian arrhythmicity, cognitive deficits, and accelerated age-dependent decline in adult neurogenesis as a consequence of increased oxidative stress. However, it is not yet known if the impaired adult neurogenesis is due to circadian disruption or to loss of the Bmal1 gene function. Therefore, we investigated oxidative stress and adult neurogenesis of the two principle neurogenic niches, the hippocampal subgranular zone and the subventricular zone in mice with a forebrain specific deletion of Bmal1 (Bmal1 fKO), which show regular circadian rhythmicity. Moreover, we analyzed the morphology of the olfactory bulb, as well as olfactory function in Bmal1 fKO mice. In Bmal1 fKO mice, oxidative stress was increased in subregions of the hippocampus and the olfactory bulb but not in the neurogenic niches. Consistently, adult neurogenesis was not affected in Bmal1 fKO mice. Although Reelin expression in the olfactory bulb was higher in Bmal1 fKO mice as compared to wildtype mice (Bmal1 WT), the olfactory function was not affected. Taken together, the targeted deletion of Bmal1 in mouse forebrain neurons is associated with a regional increase in oxidative stress and increased Reelin expression in the olfactory bulb but does not affect adult neurogenesis or olfactory function.