Thalamic and Entorhinal Network Activity Differently Modulates the Functional Development of Prefrontal-Hippocampal Interactions.

Precise information flow during mnemonic and executive tasks requires the coactivation of adult prefrontal and hippocampal networks in oscillatory rhythms. This interplay emerges early in life, most likely as an anticipatory template of later cognitive performance. At neonatal age, hippocampal theta bursts drive the generation of prefrontal theta-gamma oscillations. In the absence of direct reciprocal interactions, the question arises of which feedback mechanisms control the early entrainment of prefrontal-hippocampal networks. Here, we demonstrate that prefrontal-hippocampal activity couples with discontinuous theta oscillations and neuronal firing in both lateral entorhinal cortex and ventral midline thalamic nuclei of neonatal rats. However, these two brain areas have different contributions to the neonatal long-range communication. The entorhinal cortex mainly modulates the hippocampal activity via direct axonal projections. In contrast, thalamic theta bursts are controlled by the prefrontal cortex via mutual projections and contribute to hippocampal activity. Thus, the neonatal prefrontal cortex modulates the level of hippocampal activation by directed interactions with the ventral midline thalamus. Similar to the adult task-related communication, theta-band activity ensures the feedback control of long-range coupling in the developing brain.Significance statementMemories are encoded by finely tuned interactions within large-scale neuronal networks. This cognitive performance is not inherited, but progressively matures in relationship with the establishment of long-range coupling in the immature brain. The hippocampus initiates and unidirectionally drives the oscillatory entrainment of neonatal prefrontal cortex, yet feedback interactions that precisely control this early communication are still unresolved. Here, we identified distinct roles of entorhinal cortex and ventral midline thalamus for the functional development of prefrontal-hippocampal interactions. While entorhinal oscillations modulate the hippocampal activity by timing the neuronal firing via monosynaptic afferents, thalamic nuclei act as a relay station routing prefrontal activation back to hippocampus. Understanding the mechanisms of network maturation represents the prerequisite for assessing circuit dysfunction in neurodevelopmental disorders

From Shortage to Surge : A Developmental Switch in Hippocampal-Prefrontal Coupling in a Gene-Environment Model of Neuropsychiatric Disorders

Cognitive deficits represent a major burden of neuropsychiatric disorders and result in part from abnormal communication within hippocampal-prefrontal circuits. While it has been hypothesized that this network dysfunction arises during development, long before the first clinical symptoms, experimental evidence is still missing. Here, we show that pre-juvenile mice mimicking genetic and environmental risk factors of disease (dual-hit GE mice) have poorer recognition memory that correlates with augmented coupling by synchrony and stronger directed interactions between prefrontal cortex and hippocampus. The network dysfunction emerges already during neonatal development, yet it initially consists in a diminished hippocampal theta drive and consequently, a weaker and disorganized entrainment of local prefrontal circuits in discontinuous oscillatory activity in dual-hit GE mice when compared with controls. Thus, impaired maturation of functional communication within hippocampal-prefrontal networks switching from hypo- to hyper-coupling may represent a mechanism underlying the pathophysiology of cognitive deficits in neuropsychiatric disorders.Peer reviewe

The role of nitric oxide in the nucleus accumbens

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Data Management Plan: Early-life stress and psychiatric disorders: Role of the stress axis on the development of the serotonergic system in depression and anxiety disorders

Data Management Plan for Academy of Finland, 27.09.2016 This project will investigate the effect of birth asphyxia as a risk factor for mental disorders on the functional development of the serotonergic system in an animal model. Using most electrophysiological measurements, I will address if birth asphyxia increases the firing activity of serotonergic neurons and alters how serotonin release is controlled. I will test if this is mediated by the activation of the stress axis by birth asphyxia and the resulting hyperelevated levels of the stress hormone arginine vasopressin. Finally, I will explore if birth asphyxia alters long-range interactions in the developing brain and if these could be mediated by altered serotonergic tone. The data I will collect are mostly time series of brain activity in vitro and in vivo which will generate large volumes of data. I will analyse these with appropriate methods to answer the questions as mentioned above

High-frequency stimulation of the subthalamic nucleus modulates neuronal activity in the lateral habenula nucleus

High frequency stimulation (HFS) of the subthalamic nucleus (STN) is often used to treat movement disability in advanced Parkinson's disease, but some patients experience debilitating psychiatric effects including depression. Interestingly, HFS of the STN modulates 5-HT neurons in the dorsal raphe nucleus (DRN) which are linked to depression, but the neural substrate of this effect is unknown. Here we tested the effect of STN stimulation on neuronal activity in the lateral habenula nucleus (LHb), an important source of input to DRN 5-HT neurons and also a key controller of emotive behaviours. LHb neurons were monitored in anaesthetised rats using single unit extracellular recording, and localisation within the LHb was confirmed by juxtacellular labelling. HFS of the STN (130 Hz) evoked rapid changes in the firing rate of the majority of LHb neurons tested (38 of 68). Some LHb neurons (19/68) were activated by HFS while others (19/68), distinguished by a higher basal firing rate, were inhibited. LHb neurons that project to the DRN were identified using antidromic activation and collision testing (n=17 neurons). Some of these neurons (5/17) were also excited by HFS of the STN, and others (7/17) were inhibited although this was only a statistical trend. In summary, HFS of the STN modulated the firing of LHb neurons, including those projecting to the DRN. The data identify that the STN impacts on the LHb-DRN pathway. Moreover, this pathway may be part of the circuitry mediating the psychiatric effects of STN stimulation experienced by patients with Parkinson's disease. This article is protected by copyright. All rights reserved

Thalamic and Entorhinal Network Activity Differently Modulates the Functional Development of Prefrontal–Hippocampal Interactions

Precise information flow during mnemonic and executive tasks requires the coactivation of adult prefrontal and hippocampal networks in oscillatory rhythms. This interplay emerges early in life, most likely as an anticipatory template of later cognitive performance. At neonatal age, hippocampal theta bursts drive the generation of prefrontal theta-gamma oscillations. In the absence of direct reciprocal interactions, the question arises of which feedback mechanisms control the early entrainment of prefrontal-hippocampal networks. Here, we demonstrate that prefrontal-hippocampal activity couples with discontinuous theta oscillations and neuronal firing in both lateral entorhinal cortex and ventral midline thalamic nuclei of neonatal rats. However, these two brain areas have different contributions to the neonatal long-range communication. The entorhinal cortex mainly modulates the hippocampal activity via direct axonal projections. In contrast, thalamic theta bursts are controlled by the prefrontal cortex via mutual projections and contribute to hippocampal activity. Thus, the neonatal prefrontal cortex modulates the level of hippocampal activation by directed interactions with the ventral midline thalamus. Similar to the adult task-related communication, theta-band activity ensures the feedback control of long-range coupling in the developing brain.Significance statementMemories are encoded by finely tuned interactions within large-scale neuronal networks. This cognitive performance is not inherited, but progressively matures in relationship with the establishment of long-range coupling in the immature brain. The hippocampus initiates and unidirectionally drives the oscillatory entrainment of neonatal prefrontal cortex, yet feedback interactions that precisely control this early communication are still unresolved. Here, we identified distinct roles of entorhinal cortex and ventral midline thalamus for the functional development of prefrontal-hippocampal interactions. While entorhinal oscillations modulate the hippocampal activity by timing the neuronal firing via monosynaptic afferents, thalamic nuclei act as a relay station routing prefrontal activation back to hippocampus. Understanding the mechanisms of network maturation represents the prerequisite for assessing circuit dysfunction in neurodevelopmental disorders

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

Aberrant cortical projections to amygdala GABAergic neurons contribute to developmental circuit dysfunction following early life stress

Publisher Copyright: © 2022 The Author(s)Early life stress (ELS) results in enduring dysfunction of the corticolimbic circuitry, underlying emotional and social behavior. However, the neurobiological mechanisms involved remain elusive. Here, we have combined viral tracing and electrophysiological techniques to study the effects of maternal separation (MS) on frontolimbic connectivity and function in young (P14-21) rats. We report that aberrant prefrontal inputs to basolateral amygdala (BLA) GABAergic interneurons transiently increase the strength of feed-forward inhibition in the BLA, which raises LTP induction threshold in MS treated male rats. The enhanced GABAergic activity after MS exposure associates with lower functional synchronization within prefrontal-amygdala networks in vivo. Intriguingly, no differences in these parameters were detected in females, which were also resistant to MS dependent changes in anxiety-like behaviors. Impaired plasticity and synchronization during the sensitive period of circuit refinement may contribute to long-lasting functional changes in the prefrontal-amygdaloid circuitry that predispose to neuropsychiatric conditions later on in life.Peer reviewe