Serotonin regulation of behavior via large-scale neuromodulation of serotonin receptor networks

Salvan, Piergiorgio; Fonseca, Madalena S.; Winkler, Anderson M.; Beauchamp, Antoine; Lerch, Jason P.; Johansen‐Berg, Heidi

doi:10.1038/s41593-022-01213-3

Cited by 34 publications

(19 citation statements)

References 83 publications

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“…Finally, we studied how the functional topography of the hippocampus is reflected in macroscale cortical networks and explicitly investigated how the two established hippocampal axes map onto the cortex. We used dual-regression 50,51 to determine the individual contribution of the two orthogonal hippocampal gradients to cortical connectivity ( Figure 3A ).…”

Section: Resultsmentioning

confidence: 99%

Hippocampal connectivity patterns echo macroscale cortical evolution in the primate brain

Eichert,

DeKraker,

Howard

et al. 2023

Preprint

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The hippocampus is involved in numerous cognitive functions, some of which have uniquely human aspects, such as autobiographical memory. Hippocampal anatomy, however, is typically considered conserved across primates and its evolutionary diversification is rarely studied. Comparing hippocampal structure and function is, therefore, critical for understanding human brain architecture. Here, we developed a novel comparative framework to study the hippocampus across species characterising its geometry, microstructure, and functional network embedding. In humans and macaques, we generated a new comparative space that represents the hippocampus as an unfolded surface, which respects its sheet-like anatomy. We mapped histological and MRI-derived markers of microstructure to the hippocampal surface and integrated it with low-dimensional embedding of resting-state MRI connectivity data. Our results demonstrate that the micro– and macro-structural organisation of the hippocampus are overall conserved in both species, showing consistent anterior-posterior and subfield-to-subfield differentiation. Furthermore, while hippocampal functional organisation also follows anterior-posterior trends in both species, hippocampal functional connectivity markedly reflected evolutionary reconfiguration of transmodal networks, in particular the default-mode network. Specifically, the inferior parietal lobe in the macaque mirrors an incomplete integration of the default mode network in non-human primates. By combining fine-grained anatomical investigation with large-scale functional imaging, we showed that microstructurally preserved regions like the hippocampus may still undergo functional reconfiguration, due to their embedding in higher-order association networks.SummaryWhile the hippocampus is key for uniquely human cognitive abilities, it is also a phylogenetically old cortex and paradoxically considered evolutionarily preserved. Here, we introduce a comparative framework to quantify preservation and reconfiguration of hippocampal organisation in primate evolution, by analysing the hippocampus as an unfolded cortical surface that is geometrically matched across species. Our findings revealed an overall conservation of hippocampal macro– and micro-structure, showing anterior-posterior and, perpendicularly, subfield-related organisational axes in both humans and macaques. However, while functional organisation in both species also followed an anterior-posterior axis, the latter showed a marked evolutionary reconfiguration, which mirrors a rudimentary integration of the default-mode-network in non-human primates. Our findings suggest that microstructurally preserved regions like the hippocampus may still undergo functional reconfiguration in primate evolution, due to their embedding in heteromodal association networks.

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Section: Resultsmentioning

confidence: 99%

Hippocampal connectivity patterns echo macroscale cortical evolution in the primate brain

Eichert,

DeKraker,

Howard

et al. 2023

Preprint

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“…Supporting this concept, inhibition of norepinephrine reuptake improves motor learning in healthy adults, 77 and norepinephrine modulates cortical dopamine 78 . Serotonin is also a potent modulator of several cortical neurochemical systems and brain networks 79,80 . Cognitive and somatomotor cortical systems interact extensively in the healthy brain, 81–85 and breakdowns of these cognitive–somatomotor interactions in PD are related to worsened performance on motor tests and higher risk of debilitating falls 32,33,86,87 .…”

Section: Discussionmentioning

confidence: 99%

“…78 Serotonin is also a potent modulator of several cortical neurochemical systems and brain networks. 79,80 Cognitive and somatomotor cortical systems interact extensively in the healthy brain, [81][82][83][84][85] and breakdowns of these cognitive-somatomotor interactions in PD are related to worsened performance on motor tests and higher risk of debilitating falls. 32,33,86,87 Multimodal studies combining neurochemical imaging with task-based functional investigations of cognitive-somatomotor interactions will be useful in understanding these relationships in more detail in patients with PD.…”

Section: Discussionmentioning

confidence: 99%

Alterations of Cortical Structure and Neurophysiology in Parkinson's Disease Are Aligned with Neurochemical Systems

Wiesman,

da Silva Castanheira,

Fon

et al. 2024

Annals of Neurology

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ObjectiveParkinson's disease (PD) affects the structural integrity and neurophysiological signaling of the cortex. These alterations are related to the motor and cognitive symptoms of the disease. How these changes are related to the neurochemical systems of the cortex is unknown.MethodsWe used T1‐weighted MRI and magnetoencephalography to measure cortical thickness and task‐free neurophysiological activity in patients with idiopathic PD (NMEG = 79; NMRI = 65) and matched healthy controls (NMEG = 65; NMRI = 37). Using linear mixed‐effects models, we examine the topographical alignment of cortical structural and neurophysiological alterations in PD with cortical atlases of 19 neurotransmitter receptor and transporter densities.ResultsWe found that neurophysiological alterations in PD occur primarily in brain regions rich in acetylcholinergic, serotonergic, and glutamatergic systems, with protective implications for cognitive and psychiatric symptoms. In contrast, cortical thinning occurs preferentially in regions rich in noradrenergic systems, and the strength of this alignment relates to motor deficits.InterpretationThis study shows that the spatial organization of neurophysiological and structural alterations in PD is relevant for non‐motor and motor impairments. The data also advance the identification of the neurochemical systems implicated. The approach uses novel nested atlas modeling methodology that is transferrable to research in other neurological and neuropsychiatric diseases and syndromes.This article is protected by copyright. All rights reserved.

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“…Neuromodulatory systems may manage these disparate activity patterns, by dampening down some segments and stimulating others under different conditions (67)(68)(69)(70)(71)(72)(73)(74). ELA is frequently hypothesized to disrupt monoaminergic modulation of brain-states (6-8, 75, 76).…”

Section: Discussionmentioning

confidence: 99%

Reconfiguration of brain-wide neural activity after early life adversity

Uselman,

Jacobs,

Bearer

2023

Preprint

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Early life adversity (ELA) predisposes individuals to both physical and mental disorders lifelong. How ELA affects brain function leading to this vulnerability is under intense investigation. Research has begun to shed light on ELA effects on localized brain regions within defined circuits. However, investigations into brain-wide neural activity that includes multiple localized regions, determines relationships of activity between regions and identifies shifts of activity in response to experiential conditions is necessary. Here, we performed longitudinal manganese-enhanced magnetic resonance imaging (MEMRI) to image the brain in normally reared or ELA-exposed adults. Images were captured in the freely moving home cage condition, and short- and long-term after naturalistic threat. Images were analyzed with new computational methods, including automated segmentation and fractional activation or difference volumes. We found that neural activity was increased after ELA compared to normal rearing in multiple brain regions, some of which are involved in defensive and/or reward circuitry. Widely distributed patterns of neural activity, “brain states”, and their dynamics after threat were altered with ELA. Upon acute threat, ELA-mice retained heightened neural activity within many of these regions, and new hyperactive responses emerged in monoaminergic centers of the mid- and hindbrain. Nine days after acute threat, heightened neural activity remained within locus coeruleus and increased within posterior amygdala, ventral hippocampus, and dorso- and ventromedial hypothalamus, while reduced activity emerged within medial prefrontal cortical regions (prelimbic, infralimbic, anterior cingulate). These results reveal that functional imbalances arise between multiple brain-systems which are dependent upon context and cumulative experiences after ELA.Significance StatementEarly life adversity (ELA) is a crucial determinant of adult health. Yet, the neurobiological basis for this association remains elusive. Neural activity differs within localized brain regions in rodents who experienced ELA, yet how this localized activity contributes to overall brain states has hitherto been unknown. Here we used longitudinal manganese-enhanced MRI to reveal brain-wide activities altered by ELA compared to normal rearing. Advanced computational analyses unveiled widespread reconfiguration of segment-wise neural activity throughout the brain across a series of conditions: freely moving, experiencing threat or its aftermath. These brain state dynamics were unique to ELA. Reconfiguration of brain states after ELA, shown here for the first time, may underlie predisposition to mental and physical disorders after childhood adversity.

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Serotonin regulation of behavior via large-scale neuromodulation of serotonin receptor networks

Cited by 34 publications

References 83 publications

Hippocampal connectivity patterns echo macroscale cortical evolution in the primate brain

Hippocampal connectivity patterns echo macroscale cortical evolution in the primate brain

Alterations of Cortical Structure and Neurophysiology in Parkinson's Disease Are Aligned with Neurochemical Systems

Reconfiguration of brain-wide neural activity after early life adversity

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