Coordinated electrical activity in the olfactory bulb gates the oscillatory entrainment of entorhinal networks in neonatal mice.

Although the developmental principles of sensory and cognitive processing have been extensively investigated, their synergy has been largely neglected. During early life, most sensory systems are still largely immature. As a notable exception, the olfactory system is functional at birth, controlling mother-offspring interactions and neonatal survival. Here, we elucidate the structural and functional principles underlying the communication between olfactory bulb (OB) and lateral entorhinal cortex (LEC)-the gatekeeper of limbic circuitry-during neonatal development. Combining optogenetics, pharmacology, and electrophysiology in vivo with axonal tracing, we show that mitral cell-dependent discontinuous theta bursts in OB drive network oscillations and time the firing in LEC of anesthetized mice via axonal projections confined to upper cortical layers. Acute pharmacological silencing of OB activity diminishes entorhinal oscillations, whereas odor exposure boosts OB-entorhinal coupling at fast frequencies. Chronic impairment of olfactory sensory neurons disrupts OB-entorhinal activity. Thus, OB activity shapes the maturation of entorhinal circuits.

Bursting mitral cells time the oscillatory coupling between olfactory bulb and entorhinal networks in neonatal mice.

KEY POINTS: During early postnatal development, mitral cells show either irregular bursting or non-bursting firing patterns Bursting mitral cells preferentially fire during theta bursts in the neonatal olfactory bulb, being locked to the theta phase Bursting mitral cells preferentially fire during theta bursts in the neonatal lateral entorhinal cortex and are temporally related to both respiration rhythm- and theta phase Bursting mitral cells act as a cellular substrate of the olfactory drive that promotes the oscillatory entrainment of entorhinal networks ABSTRACT: Shortly after birth, the olfactory system provides not only the main source of environmental inputs to blind, deaf, non-whisking and motorically-limited rodents, but also the drive boosting the functional entrainment of limbic circuits. However, the cellular substrate of this early communication remains largely unknown. Here, we combine in vivo and in vitro patch-clamp and extracellular recordings to reveal the contribution of mitral cell (MC) firing to early patterns of network activity in both the neonatal olfactory bulb (OB) and the lateral entorhinal cortex (LEC), the gatekeeper of limbic circuits. We show that MCs predominantly fire either in an irregular bursting or non-bursting pattern during discontinuous theta events in the OB. However, the temporal spike-theta phase coupling is stronger for bursting than non-bursting MCs. In line with the direct OB-to-LEC projections, both bursting and non-bursting discharge augments during co-ordinated patterns of entorhinal activity, albeit with higher magnitude for bursting MCs. For these neurons, temporal coupling to the discontinuous theta events in the LEC is stronger. Thus, bursting MCs might drive the entrainment of the OB-LEC network during neonatal development.

Electrical stimulation of the ventral tegmental area evokes sleep-like state transitions under urethane anaesthesia in the rat medial prefrontal cortex via dopamine D1 -like receptors.

The role of dopamine in regulating sleep-state transitions during, both natural sleep and under anaesthesia, is still unclear. Recording in vivo in the rat mPFC under urethane anaesthesia, we observed predominantly slow wave activity (SWA) of <1 Hz in the local field potential interrupted by occasional spontaneous transitions to a low-amplitude-fast (LAF) pattern of activity. During periods of SWA, transitions to LAF activity could be rapidly and consistently evoked by electrical stimulation of the ventral tegmental area (VTA). Spontaneous LAF activity, and that evoked by stimulation of the VTA, consisted of fast oscillations similar to those seen in the rapid eye movement (REM)-like sleep state. Spontaneous and VTA stimulation-evoked LAF activity occurred simultaneously along the dorsoventral extent of all mPFC subregions. Evoked LAF activity depended on VTA stimulation current and could be elicited using either regular (25-50 Hz) or burst stimulation patterns and was reproducible upon repeated stimulation. Simultaneous extracellular single-unit recordings showed that during SWA, presumed pyramidal cells fired phasically and almost exclusively on the Up state, while during both spontaneous and VTA-evoked LAF activity, they fired tonically. The transition to LAF activity evoked by VTA stimulation depended on dopamine D1 -like receptor activation as it was almost completely blocked by systemic administration of the D1 -like receptor antagonist SCH23390. Overall, our data demonstrate that activation of dopamine D1 -like receptors in the mPFC is important for regulating sleep-like state transitions.

Dorsal vs. ventral differences in fast Up-state-associated oscillations in the medial prefrontal cortex of the urethane-anesthetized rat.

Cortical slow oscillations (0.1-1 Hz), which may play a role in memory consolidation, are a hallmark of non-rapid eye movement (NREM) sleep and also occur under anesthesia. During slow oscillations the neuronal network generates faster oscillations on the active Up-states and these nested oscillations are particularly prominent in the PFC. In rodents the medial prefrontal cortex (mPFC) consists of several subregions: anterior cingulate cortex (ACC), prelimbic (PrL), infralimbic (IL), and dorsal peduncular cortices (DP). Although each region has a distinct anatomy and function, it is not known whether slow or fast network oscillations differ between subregions in vivo. We have simultaneously recorded slow and fast network oscillations in all four subregions of the rodent mPFC under urethane anesthesia. Slow oscillations were synchronous between the mPFC subregions, and across the hemispheres, with no consistent amplitude difference between subregions. Delta (2-4 Hz) activity showed only small differences between subregions. However, oscillations in the spindle (6-15 Hz)-, beta (20-30 Hz), gamma (30-80 Hz)-, and high-gamma (80-150 Hz)-frequency bands were consistently larger in the dorsal regions (ACC and PrL) compared with ventral regions (IL and DP). In dorsal regions the peak power of spindle, beta, and gamma activity occurred early after onset of the Up-state. In the ventral regions, especially the DP, the oscillatory power in the spindle-, beta-, and gamma-frequency ranges peaked later in the Up-state. These results suggest variations in fast network oscillations within the mPFC that may reflect the different functions and connectivity of these subregions.NEW & NOTEWORTHY We demonstrate, in the urethane-anesthetized rat, that within the medial prefrontal cortex (mPFC) there are clear subregional differences in the fast network oscillations associated with the slow oscillation Up-state. These differences, particularly between the dorsal and ventral subregions of the mPFC, may reflect the different functions and connectivity of these subregions.

Neural Correlates of Anesthesia in Newborn Mice and Humans.

Monitoring the hypnotic component of anesthesia during surgeries is critical to prevent intraoperative awareness and reduce adverse side effects. For this purpose, electroencephalographic (EEG) methods complementing measures of autonomic functions and behavioral responses are in use in clinical practice. However, in human neonates and infants existing methods may be unreliable and the correlation between brain activity and anesthetic depth is still poorly understood. Here, we characterized the effects of different anesthetics on brain activity in neonatal mice and developed machine learning approaches to identify electrophysiological features predicting inspired or end-tidal anesthetic concentration as a proxy for anesthetic depth. We show that similar features from EEG recordings can be applied to predict anesthetic concentration in neonatal mice and humans. These results might support a novel strategy to monitor anesthetic depth in human newborns.

Greater intermanual transfer in the elderly suggests age-related bilateral motor cortex activation is compensatory.

Hemispheric lateralization of movement control diminishes with age; whether this is compensatory or maladaptive is debated. The authors hypothesized that if compensatory, bilateral activation would lead to greater intermanual transfer in older subjects learning tasks that activate the cortex unilaterally in young adults. They studied 10 young and 14 older subjects, learning a unimanual visuomotor task comprising a feedforward phase, where there is unilateral cortical activation in young adults, and a feedback phase, which activates the cortex bilaterally in both age groups. Increased intermanual transfer was demonstrated in older subjects during feedforward learning, with no difference between groups during feedback learning. This finding is consistent with bilateral cortical activation being compensatory to maintain performance despite declining computational efficiency in neural networks.

Pharmacogenetic stimulation of cholinergic pedunculopontine neurons reverses motor deficits in a rat model of Parkinson's disease.

BACKGROUND: Patients with advanced Parkinson's disease (PD) often present with axial symptoms, including postural- and gait difficulties that respond poorly to dopaminergic agents. Although deep brain stimulation (DBS) of a highly heterogeneous brain structure, the pedunculopontine nucleus (PPN), improves such symptoms, the underlying neuronal substrate responsible for the clinical benefits remains largely unknown, thus hampering optimization of DBS interventions. Choline acetyltransferase (ChAT)::Cre(+) transgenic rats were sham-lesioned or rendered parkinsonian through intranigral, unihemispheric stereotaxic administration of the ubiquitin-proteasomal system inhibitor, lactacystin, combined with designer receptors exclusively activated by designer drugs (DREADD), to activate the cholinergic neurons of the nucleus tegmenti pedunculopontine (PPTg), the rat equivalent of the human PPN. We have previously shown that the lactacystin rat model accurately reflects aspects of PD, including a partial loss of PPTg cholinergic neurons, similar to what is seen in the post-mortem brains of advanced PD patients. RESULTS: In this manuscript, we show that transient activation of the remaining PPTg cholinergic neurons in the lactacystin rat model of PD, via peripheral administration of the cognate DREADD ligand, clozapine-N-oxide (CNO), dramatically improved motor symptoms, as was assessed by behavioral tests that measured postural instability, gait, sensorimotor integration, forelimb akinesia and general motor activity. In vivo electrophysiological recordings revealed increased spiking activity of PPTg putative cholinergic neurons during CNO-induced activation. c-Fos expression in DREADD overexpressed ChAT-immunopositive (ChAT+) neurons of the PPTg was also increased by CNO administration, consistent with upregulated neuronal activation in this defined neuronal population. CONCLUSIONS: Overall, these findings provide evidence that functional modulation of PPN cholinergic neurons alleviates parkinsonian motor symptoms.

Neonatal hypoxia-ischemia impairs juvenile recognition memory by disrupting the maturation of prefrontal-hippocampal networks.

High-prevalence/low-severity cognitive deficits represent the life-long burden of a perinatal hypoxic­ischemic (HI) insult. They have been proposed to result from dysmaturation of prelimbic-hippocampal networks, which account for mnemonic and executive performance. Already at neonatal age the communication within these networks is largely reduced after an early HI insult with mild/moderate structural outcome. However, the longlasting consequences of the neonatal network dysfunction remain unknown. Here,we combine MRI and electrophysiology in vivo with behavioral testing to assess the effects of an early HI insult on the structure and function of prelimbic-hippocampal networks and on related cognitive abilities of juvenile rats. Despite the absence of lesions over the prelimbic cortex (PL) and hippocampus (HP), juvenile rats experiencing an early HI have lower performance in item and temporal order recognition memory. These cognitive deficits do not result from delayed somatic development or increased locomotion or anxiety. More likely, abnormal activity patterns and interactions within prelimbic-hippocampal networks account for behavioral impairment. The early HI insult causes power reduction of the fast (12­48 Hz) network activity and diminishment of neuronal firing in the PL and HP. This weaker entrainment of local circuits at juvenile age emerges in the absence of sufficiently strong directed interactions within neonatal prelimbic-hippocampal networks. Similar developmental mechanisms may account for poorer academic achievements of HI-injured infants.