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Remarkable progress has come from whole-brain models linking anatomy and function. Paradoxically, it is not clear how a neuronal dynamical system running in the fixed human anatomical connectome can give rise to the rich changes in the functional repertoire associated with human brain function, which is impossible to explain through long-term plasticity. Neuromodulation evolved to allow for such flexibility by dynamically updating the effectivity of the fixed anatomical connectivity. Here, we introduce a theoretical framework modeling the dynamical mutual coupling between the neuronal and neurotransmitter systems. We demonstrate that this framework is crucial to advance our understanding of whole-brain dynamics by bidirectional coupling of the two systems through combining multimodal neuroimaging data (diffusion magnetic resonance imaging [dMRI], functional magnetic resonance imaging [fMRI], and positron electron tomography [PET]) to explain the functional effects of specific serotoninergic receptor (5-HT2AR) stimulation with psilocybin in healthy humans. This advance provides an understanding of why psilocybin is showing considerable promise as a therapeutic intervention for neuropsychiatric disorders including depression, anxiety, and addiction. Overall, these insights demonstrate that the whole-brain mutual coupling between the neuronal and the neurotransmission systems is essential for understanding the remarkable flexibility of human brain function despite having to rely on fixed anatomical connectivity.

The acoustic startle reflex (ASR) and prepulse inhibition of the ASR (PPI) assess the efficiency of salience processing, a fundamental brain function that is impaired in many psychiatric conditions. Both ASR and PPI depend on noradrenergic transmission, yet the modulatory role of the locus coeruleus (LC) remains controversial. Clonidine (0.05 mg/kg, i.p.), an alpha2‐adrenoreceptor agonist, strongly reduced the ASR amplitude. In contrast, chemogenetic LC inhibition only mildly suppressed the ASR and did affect the PPI in virus‐transduced rats. The canine adenovirus type 2 (CAV2)–based vector carrying a gene cassette for the expression of inhibitory receptors (hM4Di) and noradrenergic cell–specific promoter (PRSx8) had high cell‐type specificity (94.4 ± 3.1%) but resulted in heterogeneous virus transduction of DbH‐positive LC neurons (range: 9.2–94.4%). Clozapine‐N‐oxide (CNO; 1 mg/kg, i.p.), a hM4Di actuator, caused the firing cessation of hM4Di‐expressing LC neurons, yet complete inhibition of the entire population of LC neurons was not achieved. Case‐based immunohistochemistry revealed that virus injections distal (> 150 μm) to the LC core resulted in partial LC transduction, while proximal (< 50 μm) injections caused neuronal loss due to virus neurotoxicity. Neither the ASR nor PPI differed between the intact and virus‐transduced rats. Our results suggest that a residual activity of virus‐non‐transduced LC neurons might have been sufficient for mediating an unaltered ASR and PPI. Our study highlights the importance of a case‐based assessment of the virus efficiency, specificity, and neurotoxicity for targeted cell populations and of considering these factors when interpreting behavioral effects in experiments employing chemogenetic modulation. [ABSTRACT FROM AUTHOR]

The critical brain hypothesis states that the brain can benefit from operating close to a second-order phase transition. While it has been shown that several computational aspects of sensory processing (e.g., sensitivity to input) can be optimal in this regime, it is still unclear whether these computational benefits of criticality can be leveraged by neural systems performing behaviorally relevant computations. To address this question, we investigate signatures of criticality in networks optimized to perform efficient coding. We consider a spike-coding network of leaky integrateand-fire neurons with synaptic transmission delays. Previously, it was shown that the performance of such networks varies nonmonotonically with the noise amplitude. Interestingly, we find that in the vicinity of the optimal noise level for efficient coding, the network dynamics exhibit some signatures of criticality, namely, scale-free dynamics of the spiking and the presence of crackling noise relation. Our work suggests that two influential, and previously disparate theories of neural processing optimization (efficient coding and criticality) may be intimately related. [ABSTRACT FROM AUTHOR]

Spatial navigation depends on the hippocampal function, but also requires bidirectional interactions between the hippocampus (HPC) and the prefrontal cortex (PFC). The cross-regional communication is typically regulated by critical nodes of a distributed brain network. The thalamic nucleus reuniens (RE) is reciprocally connected to both HPC and PFC and may coordinate the information flow within the HPC-PFC pathway. Here we examined if RE activity contributes to the spatial memory consolidation. Rats were trained to find reward following a complex trajectory on a crossword-like maze. Immediately after each of the five daily learning sessions the RE was reversibly inactivated by local injection of muscimol. The post-training RE inactivation affected neither the spatial task acquisition nor the memory retention, which was tested after a 20-d "forgetting" period. In contrast, the RE inactivation in well-trained rats prior to the maze exposure impaired the task performance without affecting locomotion or appetitive motivation. Our results support the role of the RE in memory retrieval and/or "online" processing of spatial information, but do not provide evidence for its engagement in "off-line" processing, at least within a time window immediately following learning experience.

Experience-induced replay of neuronal ensembles occurs during hippocampal high-frequency oscillations, or ripples. Post-learning increase in ripple rate is predictive of memory recall, while ripple disruption impairs learning. Ripples may thus present a fundamental component of a neurophysiological mechanism of memory consolidation. In addition to system-level local and cross-regional interactions, a consolidation mechanism involves stabilization of memory representations at the synaptic level. Synaptic plasticity within experience-activated neuronal networks is facilitated by noradrenaline release from the axon terminals of the locus coeruleus (LC). Here, to better understand interactions between the system and synaptic mechanisms underlying "off-line" consolidation, we examined the effects of ripple-associated LC activation on hippocampal and cortical activity and on spatial memory. Rats were trained on a radial maze; after each daily learning session neural activity was monitored for 1 h via implanted electrode arrays. Immediately following "on-line" detection of ripple, a brief train of electrical pulses (0.05 mA) was applied to LC. Low-frequency (20 Hz) stimulation had no effect on spatial learning, while higher-frequency (100 Hz) trains transiently blocked generation of ripple-associated cortical spindles and caused a reference memory deficit. Suppression of synchronous ripple/spindle events appears to interfere with hippocampal-cortical communication, thereby reducing the efficiency of "off-line" memory consolidation.