Neonatal cholinergic lesion alters the acoustic structure of infant rat vocalization but not the early cognitive development.

Cholinergic innervation is critically required for cytoarchitectonic maturation of the cerebral cortex as well as functional assembling of neuronal networks and their behavioral readout. Selective lesion of cortically projecting cholinergic neurons initiated immediately after birth by the immunotoxin 192 IgG-saporin (SAP) led to abnormal wiring of prefrontal-hippocampal networks, yet the neurobehavioral and cognitive consequences of this impairment are still poorly understood. Here, we show that partial cholinergic depletion initiated at birth did not impact the general development of rat pups during the first 2 postnatal weeks, their homing behavior, and the maturation of recognition memory. However, the acoustic structure of infant ultrasonic vocalization was significantly affected by SAP, indicating that early neurobehavioral development relies on intact cholinergic drive. This altered vocalization did not elicit differential maternal care, suggesting that the previously reported SAP-induced behavioral deficits at adulthood are the direct result of cholinergic depletion rather than of abnormal mother-pup interactions.

Cholinergic control in developing prefrontal-hippocampal networks.

The cholinergic drive enhances input processing in attentional and mnemonic context by interacting with the activity of prefrontal-hippocampal networks. During development, acetylcholine modulates neuronal proliferation, differentiation, and synaptic plasticity, yet its contribution to the maturation of cognitive processing resulting from early entrainment of neuronal networks in oscillatory rhythms remains widely unknown. Here we show that cholinergic projections growing into the rat prefrontal cortex (PFC) toward the end of the first postnatal week boost the generation of nested gamma oscillations superimposed on discontinuous spindle bursts by acting on functional muscarinic but not nicotinic receptors. Although electrical stimulation of cholinergic nuclei increased the occurrence of nested gamma spindle bursts by 41%, diminishment of the cholinergic input by either blockade of the receptors or chronic immunotoxic lesion had the opposite effect. This activation of locally generated gamma episodes by direct cholinergic projections to the PFC was accompanied by indirect modulation of underlying spindle bursts via cholinergic control of hippocampal theta activity. With ongoing maturation and switch of network activity from discontinuous bursts to continuous theta-gamma rhythms, accumulating cholinergic projections acting on both muscarinic and nicotinic receptors mediated the transition from high-amplitude slow to low-amplitude fast rhythms in the PFC. By exerting multiple actions on the oscillatory entrainment of developing prefrontal-hippocampal networks, the cholinergic input may refine them for later gating processing in executive and mnemonic tasks.

Neonatal hippocampal lesion alters the functional maturation of the prefrontal cortex and the early cognitive development in pre-juvenile rats.

Mnemonic and executive performance is encoded into activity patterns of complex neuronal networks. Lesion studies revealed that adult recognition memory critically depends on the activation of the prefrontal cortex (PFC) and hippocampus (HP). However, its developmental profile remains poorly elucidated. We previously showed the rat PFC and HP are functionally coupled in theta- and gamma-band oscillations during neonatal [postnatal day (P) 5-8] and pre-juvenile (P10-15) stages of development. Here, we assess the behavioral readout of this early prefrontal-hippocampal activation by investigating the ontogeny and the mechanisms of novelty detection and recognition memory in relationship to the functional integrity of the PFC and HP. Excitotoxic lesion of the HP at birth led to abnormal oscillatory entrainment of the PFC throughout neonatal and pre-juvenile development. Although the onset of novelty detection correlated rather with the maturation of sensory perception and motor skills than with hippocampal integrity, the pre-juvenile performance in item, spatial and temporal order recognition memory significantly decreased after HP lesion at birth. This poorer performance does result neither from abnormal developmental milestones and locomotion nor from increased anxiety. Thus, novelty recognition in rat emerges during the second postnatal week and requires functional integrity of communication within neuronal networks including the PFC and HP.