Nearly half a century has passed since the discovery of cytoplasmic inheritance of human chloramphenicol resistance. The inheritance was then revealed to take place maternally by mitochondrial DNA (mtDNA). Later, a number of mutations in mtDNA were identified as a cause of severe inheritable metabolic diseases with neurological manifestation, and the impairment of mitochondrial functions has been probed in the pathogenesis of a wide range of illnesses including neurodegenerative diseases. Recently, a growing number of preclinical studies have revealed that animal behaviors are influenced by the impairment of mitochondrial functions and possibly by the loss of mitochondrial stress resilience. Indeed, as high as 54% of patients with one of the most common primary mitochondrial diseases, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome, present psychiatric symptoms including cognitive impairment, mood disorder, anxiety, and psychosis. Mitochondria are multifunctional organelles which produce cellular energy and play a major role in other cellular functions including homeostasis, cellular signaling, and gene expression, among others. Mitochondrial functions are observed to be compromised and to become less resilient under continuous stress. Meanwhile, stress and inflammation have been linked to the activation of the tryptophan (Trp)–kynurenine (KYN) metabolic system, which observably contributes to the development of pathological conditions including neurological and psychiatric disorders. This review discusses the functions of mitochondria and the Trp-KYN system, the interaction of the Trp-KYN system with mitochondria, and the current understanding of the involvement of mitochondria and the Trp-KYN system in preclinical and clinical studies of major neurological and psychiatric diseases.

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Mitochondrial Impairment: A Common Motif in Neuropsychiatric Presentation? The Link to the Tryptophan–Kynurenine Metabolic System

Kynurenic acid (KYNA) is an endogenous tryptophan (Trp) metabolite known to possess neuroprotective property. KYNA plays critical roles in nociception, neurodegeneration, and neuroinflammation. A lower level of KYNA is observed in patients with neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases or psychiatric disorders such as depression and autism spectrum disorders, whereas a higher level of KYNA is associated with the pathogenesis of schizophrenia. Little is known about the optimal concentration for neuroprotection and the threshold for neurotoxicity. In this study the effects of KYNA on memory functions were investigated by passive avoidance test in mice. Six different doses of KYNA were administered intracerebroventricularly to previously trained CFLP mice and they were observed for 24 h. High doses of KYNA (i.e., 20–40 μg/2 μL) significantly decreased the avoidance latency, whereas a low dose of KYNA (0.5 μg/2 μL) significantly elevated it compared with controls, suggesting that the low dose of KYNA enhanced memory function. Furthermore, six different receptor blockers were applied to reveal the mechanisms underlying the memory enhancement induced by KYNA. The series of tests revealed the possible involvement of the serotonergic, dopaminergic, α and β adrenergic, and opiate systems in the nootropic effect. This study confirmed that a low dose of KYNA improved a memory component of cognitive domain, which was mediated by, at least in part, four systems of neurotransmission in an animal model of learning and memory.

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Memory Enhancement with Kynurenic Acid and Its Mechanisms in Neurotransmission

Abstract Understanding transient dynamics of the autonomic nervous system during fear learning remains a critical step to translate basic research into treatment of fear‐related disorders. In humans, it has been demonstrated that fear learning typically elicits transient heart rate deceleration. However, classical analyses of heart rate variability (HRV) fail to disentangle the contribution of parasympathetic and sympathetic systems, and crucially, they are not able to capture phasic changes during fear learning. Here, to gain deeper insight into the physiological underpinnings of fear learning, a novel frequency‐domain analysis of heart rate was performed using a short‐time Fourier transform, and instantaneous spectral estimates extracted from a point‐process modeling algorithm. We tested whether spectral transient components of HRV, used as a noninvasive probe of sympathetic and parasympathetic mechanisms, can dissociate between fear conditioned and neutral stimuli. We found that learned fear elicited a transient heart rate deceleration in anticipation of noxious stimuli. Crucially, results revealed a significant increase in spectral power in the high frequency band when facing the conditioned stimulus, indicating increased parasympathetic (vagal) activity, which distinguished conditioned and neutral stimuli during fear learning. Our findings provide a proximal measure of the involvement of cardiac vagal dynamics into the psychophysiology of fear learning and extinction, thus offering new insights for the characterization of fear in mental health and illness.

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Characterizing cardiac autonomic dynamics of fear learning in humans

Following introduction of the monoamine oxidase type B inhibitor selegiline for the treatment of Parkinson’s disease (PD), discovery of the action mechanism of Alzheimer’s disease-modifying agent memantine, the role of iron in PD, and the loss of electron transport chain complex I in PD, and development of the concept of clinical neuroprotection, Peter Riederer launched one of the most challenging research project neurodevelopmental aspects of neuropsychiatric disorders. The neurodevelopmental theory holds that a disruption of normal brain development in utero or during early life underlies the subsequent emergence of neuropsychiatric symptoms during later life. Indeed, the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition and the International Classification of Diseases, 11th Revision categorize autism spectrum disorder and attention deficit hyperactivity disorder in neurodevelopmental disorders (NDDs). More and more evidence, especially from preclinical studies, is revealing that neurodevelopmental pathology is not limited to the diagnostic class above, but also contributes to the development of other psychiatric disorders such as schizophrenia, bipolar disorder, and obsessive–compulsive disorder as well as neurodegenerative diseases such as PD and Huntington’s disease. Preclinical animal research is taking a lead in understanding the pathomechanisms of NDDs, searching for novel targets, and developing new neuroprotective agents against NDDs. This narrative review discusses emerging evidence of the neurodevelopmental etiology of neuropsychiatric disorders, recent advances in modelling neurodevelopmental pathogenesis, potential strategies of clinical neuroprotection using novel kynurenine metabolites and analogues, and future research direction for NDDs. 

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Modelling the neurodevelopmental pathogenesis in neuropsychiatric disorders. Bioactive kynurenines and their analogues as neuroprotective agents—in celebration of 80th birthday of Professor Peter Riederer

Emotions are able to impact our ability to control our behaviors. However, it is not clear whether emotions play a detrimental or an advantageous effect on action control and whether the valence of the emotional stimuli differently affects such motor abilities. One way to measure reactive inhibitory control is the stop-signal task (SST), which estimates the ability to cancel outright a response to the presentation of a stop signal by means of the stop signal reaction times (SSRT). Impaired as well as facilitated action control has been found when faced with emotional stimuli such as stop signals in SSTs and mixed results were observed for positive versus negative stimuli. Here, we aimed to investigate these unresolved issues more deeply. Action control capabilities were tested in 60 participants by means of a SST, in which the stop signals were represented by a fearful and a happy body posture together with their neutral counterpart. Results showed that both positive and negative body postures enhanced the ability to suppress an ongoing action compared to neutral body postures. These results demonstrate that emotional valence-independent emotional stimuli facilitate action control and suggest that emotional stimuli may trigger increased sensory representation and/or attentional processing that may have promote stop-signal processing and hence improved inhibitory performance.

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Stopping in (e)motion: Reactive action inhibition when facing valence-independent emotional stimuli

The ability to adaptively follow conspecific eye movements is crucial for establishing shared attention and survival. Indeed, in humans, interacting with the gaze direction of others causes the reflexive orienting of attention and the faster object detection of the signaled spatial location. The behavioral evidence of this phenomenon is called gaze-cueing. Although this effect can be conceived as automatic and reflexive, gaze-cueing is often susceptible to context. In fact, gaze-cueing was shown to interact with other factors that characterize facial stimulus, such as the kind of cue that induces attention orienting (i.e., gaze or non-symbolic cues) or the emotional expression conveyed by the gaze cues. Here, we address neuroimaging evidence, investigating the neural bases of gaze-cueing and the perception of gaze direction and how contextual factors interact with the gaze shift of attention. Evidence from neuroimaging, as well as the fields of non-invasive brain stimulation and neurologic patients, highlights the involvement of the amygdala and the superior temporal lobe (especially the superior temporal sulcus (STS)) in gaze perception. However, in this review, we also emphasized the discrepancies of the attempts to characterize the distinct functional roles of the regions in the processing of gaze. Finally, we conclude by presenting the notion of invariant representation and underline its value as a conceptual framework for the future characterization of the perceptual processing of gaze within the STS.

https://www.mdpi.com/2227-9059/10/3/627/pdf?version=1646800956

The Neurobiological Correlates of Gaze Perception in Healthy Individuals and Neurologic Patients

Since the dawn of cognitive neuroscience, emotions have been recognized to impact on several executive processes, such as action inhibition. However, the complex interplay between emotional stimuli and action control is not yet fully understood. One way to measure inhibitory control is the stop-signal task (SST), which estimates the ability to cancel outright an action to the presentation of a stop signal by means of the stop-signal reaction times (SSRTs). Impaired as well as facilitated action control has been found when faced with intrinsic emotional stimuli as stop signals in SSTs. Here, we aimed at investigating more deeply the power of negative stimuli to influence our action control, testing the hypothesis that a previously neutral stimulus [i.e., the image of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)], which has been conditioned through vicarious fear learning, has the same impact on reactive action inhibition performance as an intrinsically negative stimulus (i.e., a fearful face or body). Action control capabilities were tested in 90 participants by means of a SST, in which the stop signals were represented by different negative stimuli. Results showed that the SARS-CoV-2 image enhanced the ability to suppress an ongoing action similarly to observing fearful facial expressions or fearful body postures. Interestingly, we found that this effect was predicted by impulsivity traits: for example, the less self-control the participants had, the less they showed emotional facilitation for inhibitory performance. These results demonstrated that vicarious fear learning has a critical impact on cognitive abilities, making a neutral image as threatening as phylogenetically innate negative stimuli and able to impact on our behavioral control.

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The Influence of Vicarious Fear-Learning in “Infecting” Reactive Action Inhibition

Learning to recognize and respond to potential threats is crucial for survival. Pavlovian threat conditioning represents a key paradigm for investigating the neurobiological mechanisms of fear learning. In this review, we address the role of specific neuropharmacological adjuvants that act on neurochemical synaptic transmission, as well as on brain plasticity processes implicated in fear memory. We focus on novel neuropharmacological manipulations targeting glutamatergic, noradrenergic, and endocannabinoid systems, and address how the modulation of these neurobiological systems affects fear extinction learning in humans. We show that the administration of N-methyl-D-aspartate (NMDA) agonists and modulation of the endocannabinoid system by fatty acid amide hydrolase (FAAH) inhibition can boost extinction learning through the stabilization and regulation of the receptor concentration. On the other hand, elevated noradrenaline levels dynamically modulate fear learning, hindering long-term extinction processes. These pharmacological interventions could provide novel targeted treatments and prevention strategies for fear-based and anxiety-related disorders.

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Neuropharmacological Modulation of N-methyl-D-aspartate, Noradrenaline and Endocannabinoid Receptors in Fear Extinction Learning: Synaptic Transmission and Plasticity

Simone Battaglia

Papers

Characterizing cardiac autonomic dynamics of fear learning in humans

The Neurobiological Correlates of Gaze Perception in Healthy Individuals and Neurologic Patients

Stopping in (e)motion: Reactive action inhibition when facing valence-independent emotional stimuli

The Influence of Vicarious Fear-Learning in “Infecting” Reactive Action Inhibition

Neuropharmacological Modulation of N-methyl-D-aspartate, Noradrenaline and Endocannabinoid Receptors in Fear Extinction Learning: Synaptic Transmission and Plasticity