Olfactory entrainment of cortical-hippocampal networks during development

Abstract

Brain activity is organized in coordinated patterns, which enable local and long-range communication in neuronal networks that are important for cognitive abilities. During neonatal development, the foundation of these functional networks is formed by several interwind processes which are governed by genetic and molecular factors and are refined by early patterns of neuronal activity. During the first two postnatal weeks, discontinuous bursts of activity, often generated spontaneously in the sensory periphery, aid the refinement of neuronal circuits important for adult sensory processing. Similar activity patterns also occur in hippocampal-prefrontal circuits which are involved in cognition. Disturbance of these early activity patterns has a profound impact on adult circuits and behavioral abilities, implying a causal role of neonatal activity patterns in the functional development of these networks. Yet, to date, it is not clear whether these early patterns of coordinated activity emerge endogenously within cortical-hippocampal networks or whether they are shaped by inputs from sensory systems. Rodents are born with limited sensory abilities and remain blind, deaf, and do not whisker until the end of the second postnatal week. During this time period, newborn mice instead rely heavily on their sense of smell which is functional from birth on. Olfaction provides not only one of the first sensory experiences of newborn rodents but also instructs goal-directed behaviors and the formation of associative memories. Aside from its early functionality, the olfactory system also differs from the other sensory systems in its direct connectivity to cortical brain areas lacking the relay through the thalamus. Direct axonal projections connect the olfactory bulb with, among other brain areas, the lateral entorhinal cortex which represents a nodal point in the cortical-hippocampal circuitry. Thus, olfaction might represent a key candidate in shaping the maturation of neuronal networks involved in cognitive processing. In this thesis, I aim to shed light on the contribution of olfactory activity on the network entrainment within entorhinal-hippocampal-prefrontal circuits during neonatal development. Using a wide range of experimental techniques ranging from in vivo intra- and extracellular electrophysiology to axonal tracing we report that neonatal olfactory bulb activity is characterized by a continuous, respiration-driven slow rhythm which is accompanied by discontinuous activity patterns in the theta/beta range. Neuronal activity in the olfactory bulb further drives neuronal firing and discontinuous network activity in the developing lateral entorhinal cortex via axonal projections from mitral cells. This early network activity is only mildly affected by anesthesia and increases after olfactory stimulation. Interestingly, bursting compared to non-bursting mitral cells are temporally more tightly coupled to discontinuous network oscillations in the olfactory bulb and lateral entorhinal cortex. Thus, olfactory activity shapes network activity in the developing lateral entorhinal cortex. Additionally, we report that mitral cell activity not only shapes entorhinal networks but further entrains hippocampal and prefrontal circuits during synchronized beta oscillations. Considering the importance of cortical-hippocampal beta oscillations for memory processing, this early synchronization of the network might act as a template for long-range communication during cognitive processing. Together these findings suggest an important role of olfaction for the development of brain areas involved in cognitive processing. Having established the impact and functionality of early feedforward projections from the olfactory bulb to the cortex, we next investigated the development of feedback projections to the olfactory bulb. Sensory processing is not merely a feedforward process but depends on feedback from cortical brain areas providing information about context, attention, and prior knowledge. We show that in contrast to feedforward projections which are present from birth on, centrifugal feedback projections develop postnatally in an area-specific manner. While glutamatergic feedback projections from the piriform cortex emerge already shortly after birth, feedback from brain areas such as the lateral entorhinal cortex, ventral hippocampus, and cortical amygdala appears only at the beginning of the second postnatal week. These data suggest that olfactory processing occurs mostly independent from top-down influences at birth, but gets increasingly more modulated by cortical feedback across development. Together the here presented data show that, while the olfactory system is already functional from birth on, its connectivity and network activity is still developing. Importantly, this immature olfactory activity has a profound impact on the coordinated activity patterns in brain areas that are critical for later cognitive abilities. While many open questions remain, these data provide first insights into the role that olfactory activity plays in the maturation of the cortical-hippocampal network.