Roman Boehringer

Maternal behaviors in mammals, which are critical for offspring survival, involve complex interactions between innate neural circuits and behavioral flexibility. This flexibility depends on environmental needs and external stimuli. Recent studies suggest that social transmission plays a crucial role in the acquisition of maternal behaviors in alloparental (non-maternal) subjects, particularly highlighting visual observation for virgin female mice to acquire pup retrieval behavior. However, the extent to which these behaviors rely on social transmission versus the activation of pre-existing, latent behaviors remains unclear. Here, we systematically investigated the necessity of social observation for maternal behavior acquisition, using a social transmission pup retrieval paradigm in pup-naive virgin female mice. Following the same protocol as previous studies, we compared retrieval performance on conditions that either allowed or prevented the visual observation of maternal demonstrations. Contrary to previous findings reporting substantial differences between these conditions, we found that virgin females readily acquired pup retrieval behavior regardless of their visual access to experienced mothers. We observed no significant correlation between maternal and virgin performance after task exposure. Detailed behavioral analysis revealed that the primary difference between mothers and virgins lay on the latency to initiate the behavior, but once started, virgins complete the retrieval as fast as mothers. Together, our findings show that pup exposure is enough to activate latent behaviors, and suggest that pup retrieval might not be transmitted by visual observation.

The prefrontal cortex (PFC) plays a central role in the selection and expression of diverse social behaviors. A balance of excitation and inhibition is necessary for normal social functioning, but it remains unclear how inhibition sculpts pyramidal activity to promote specific social behaviors. To address this question, we developed a novel decision-making task in which female mice chose between interaction with a male (sociosexual stimulus) or an appetitive non-social option (milk solution). To explore the role of a task-relevant inhibitory subpopulation, we targeted neurons in the medial PFC (mPFC) expressing oxytocin receptors (OXTR neurons). Combining optogenetic inhibition of OXTR neurons with population calcium imaging of pyramidal neural activity, we found that OXTR neurons normally promote interaction with a male compared to a non-social alternative. OXTR neurons also regulate pyramidal activity, which enables a specific ensemble to represent the male option during decision-making. Computational modeling reproduced these findings through a pyramidal competition mechanism, in which regulation by OXTR neurons allows a male-representing pyramidal ensemble to effectively compete against the remaining pyramidal population to drive male choice. These results provide a candidate mechanism by which inhibition enables mPFC pyramidal activity to select for specific social behaviors and may help explain why excitation/inhibition balance is so important for social functioning.

Blood Oxygen Level-Dependent (BOLD) functional Magnetic Resonance Imaging (fMRI) allows for non-invasive, indirect recordings of neural activity across the whole brain in both humans and animals. However, the relationship between the local neural population activity and the vascular activity is not completely understood. To investigate this relationship, we present a novel MRI compatible single-photon microscope capable of measuring cellular resolution Ca ²⁺ activity of genetically defined neurons during whole-brain BOLD fMRI in awake behaving mice. Using this combined imaging approach, we found a difference in activity patterns between cells which was dependent on their location with respect to the vasculature. Notably, neurons near the vasculature showed pronounced negative activity during contralateral whisker movements at 3 Hz. In a second proof of concept experiment, we demonstrate the potential of recording both local neural activities, like those in the barrel field (SSp-bfd), and BOLD fMRI readings from interlinked brain regions. In sum, the presented technological advancement paves the way for studies examining the interplay between local brain circuits and overarching brain functions. In addition, the new approach enhances our understanding of the vascular BOLD fMRI signal, providing insights into the determinants of local neurovascular functions and the brain’s organizational framework across various scales.

The medial prefrontal cortex (mPFC) has been proposed to link sensory inputs and behavioral outputs to mediate the execution of learned behaviors. However, how such a link is implemented has remained unclear. To measure prefrontal neural correlates of sensory stimuli and learned behaviors, we performed population calcium imaging during a novel tone-signaled active avoidance paradigm in mice. We developed a novel analysis approach based on dimensionality reduction and decoding that allowed us to identify and isolate population activity patterns related the tone stimulus, learned avoidance actions and general motion. While tone-related activity was not informative about behavior, avoidance-related activity was predictive of upcoming avoidance actions. Moreover, avoidance-related activity distinguished between two different learned avoidance actions, consistent with a model in which mPFC contributes to the selection between different goal-directed actions. Overall, our results suggest that mPFC circuit dynamics transform sensory inputs into specific behavioral outputs through distributed population-level computations.

The hippocampus is critical for memory formation. The hypothalamic supramammillary nucleus (SuM) sends long-range projections to hippocampal area CA2. While the SuM-CA2 connection is critical for social memory, how this input acts on the local circuit is unknown. Using transgenic mice, we found that SuM axon stimulation elicited mixed excitatory and inhibitory responses in area CA2 pyramidal neurons (PNs). Parvalbumin-expressing basket cells were largely responsible for the feedforward inhibitory drive of SuM over area CA2. Inhibition recruited by the SuM input onto CA2 PNs increased the precision of action potential firing both in conditions of low and high cholinergic tone. Furthermore, SuM stimulation in area CA2 modulated CA1 activity, indicating that synchronized CA2 output drives a pulsed inhibition in area CA1. Hence, the network revealed here lays basis for understanding how SuM activity directly acts on the local hippocampal circuit to allow social memory encoding.

Down syndrome, the leading genetic cause of intellectual disability, results from an extra-copy of chromosome 21. Mice engineered to model this aneuploidy exhibit Down syndrome-like memory deficits in spatial and contextual tasks. While abnormal neuronal function has been identified in these models, most studies have relied on in vitro measures. Here, using in vivo recording in the Dp(16)1Yey model, we find alterations in the organization of spiking of hippocampal CA1 pyramidal neurons, including deficits in the generation of complex spikes. These changes lead to poorer spatial coding during exploration and less coordinated activity during sharp-wave ripples, events involved in memory consolidation. Further, the density of CA1 inhibitory neurons expressing neuropeptide Y, a population key for the generation of pyramidal cell bursts, were significantly increased in Dp(16)1Yey mice. Our data refine the ‘over-suppression’ theory of Down syndrome pathophysiology and suggest specific neuronal subtypes involved in hippocampal dysfunction in these model mice.