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Trauma-related disorders are debilitating psychiatric conditions that affect people who have directly or indirectly witnessed adversities. Experiencing multiple types of traumas appears to be common during childhood, and even more so during adolescence. Dramatic brain/body transformations occurring during adolescence may provide a highly responsive substrate to external stimuli and lead to trauma-related vulnerability conditions, such as internalizing (anxiety, depression, anhedonia, withdrawal) and externalizing (aggression, delinquency, conduct disorders) problems. Analyzing relations among neuronal, endocrine, immune, and biochemical signatures of trauma and internalizing and externalizing behaviors, including the role of personality traits in shaping these conducts, this review highlights that the marked effects of traumatic experience on the brain/body involve changes at nearly every level of analysis, from brain structure, function and connectivity to endocrine and immune systems, from gene expression (including in the gut) to the development of personality.

This chapter addresses how the embodiment approach may represent a unifying perspective for examining the cerebellar role in emotional behavior and psychological traits. It is not intended to be exhaustive, but rather it can be a good starting point for advancing the cerebellar neural mechanism underlying embodiment. Our goal is to provide illustrative examples of embodied emotions and psychological traits in the emerging field of emotional and cognitive cerebellum. We illustrate how the cerebellum could be an important hub in the embodiment processes, associated with empathic abilities, impaired emotional identification and expression (as occurring for example in the presence of alexithymia), and specific psychological constructs (i.e., hypnotizability).

Approach and avoidance (A/A) tendencies are stable behavioral traits in responding to rewarding and fearful stimuli. They represent the superordinate division of emotion, and individual differences in such traits are associated with disease susceptibility. The neural circuitry underlying A/A traits is retained to be the cortico-limbic pathway including the amygdala, the central hub for the emotional processing. Furthermore, A/A-specific individual differences are associated with the activity of the endocannabinoid system (ECS) and especially of CB1 receptors whose density and functionality in amygdala differ according to A/A traits. ECS markedly interacts with the immune system (IS). However, how the interplay between ECS and IS is associated with A/A individual differences is still ill-defined. To fill this gap, here we analyzed the interaction between the gene expression of ECS and immune system (IS) in relation to individual differences. To unveil the deep architecture of ECS-IS interaction, we performed cell-specific transcriptomics analysis. Differential gene expression profiling, functional enrichment, and protein–protein interaction network analyses were performed in amygdala pyramidal neurons of mice showing different A/A behavioral tendencies. Several altered pro-inflammatory pathways were identified as associated with individual differences in A/A traits, indicating the chronic activation of the adaptive immune response sustained by the interplay between endocannabinoids and the IS. Furthermore, results showed that the interaction between the two systems modulates synaptic plasticity and neuronal metabolism in individual difference-specific manner. Deepening our knowledge about ECS/IS interaction may provide useful targets for treatment and prevention of psychopathology associated with A/A traits.

Whereas emotion theorists often keep their distance from the embodied approach, theorists of embodiment tend to treat emotion as a mainly physiologic process. However, intimate links between emotions and the body suggest that emotions are privileged phenomena to attempt to reintegrate mind and body and that the body helps the mind in shaping emotional responses. To date, research has favored the cerebrum over other parts of the brain as a substrate of embodied emotions. However, given the widely demonstrated contribution of the cerebellum to emotional processing, research in affective neuroscience should consider embodiment theory as a useful approach for evaluating the cerebellar role in emotion and affect. The aim of this review is to insert the cerebellum among the structures needed to embody emotions, providing illustrative examples of cerebellar involvement in embodied emotions (as occurring in empathic abilities) and in impaired identification and expression of embodied emotions (as occurring in alexithymia).

To promote efficient explorative behaviors, subjects adaptively select spatial navigational strategies based on landmarks or a cognitive map. The hippocampus works alone or in conjunction with the dorsal striatum, both representing the neuronal underpinnings of the navigational strategies organized on the basis of different systems of spatial coordinate integration. The high expression of cannabinoid type 1 (CB1) receptors in structures related to spatial learning&mdash, such as the hippocampus, dorsal striatum and amygdala&mdash, renders the endocannabinoid system a critical target to study the balance between landmark- and cognitive map-based navigational strategies. In the present study, mice treated with the CB1-inverse agonist/antagonist AM251 or vehicle were trained on a Circular Hole Board, a task that could be solved through either navigational strategy. At the end of the behavioral testing, c-Fos immunoreactivity was evaluated in specific nuclei of the hippocampus, dorsal striatum and amygdala. AM251 treatment impaired spatial learning and modified the pattern of the performed navigational strategies as well as the c-Fos immunoreactivity in the hippocampus, dorsal striatum and amygdala. The present findings shed light on the involvement of CB1 receptors as part of the selection system of the navigational strategies implemented to efficiently solve the spatial problem.

Converging evidence highlights the role of environmentally-driven epigenetic modifications in shaping developmental trajectories, influencing personalized expression of genetic information and thus modulating vulnerability and resiliency to psychiatric diseases. The most influential epigenetic human studies are predicated on significant experimental findings in animals that have shown that brain development and function are sculpted by very early or even ancestral experiences. Animal models allow to prospectively manipulate under controlled conditions the exposures to aversive or permissive environment and to evaluate immediate, long-term and transgenerational consequences on candidate gene expression and behavior. This chapter reports animal studies focused on the role of postnatal maternal care in inducing stable individual differences in the offspring, and on the consequences of the exposure to aversive and permissive environments for neurobiology and behavior.

Food restriction is a robust nongenic, nonsurgical and nonpharmacologic intervention known to improve health and extend lifespan in various species. Food is considered the most essential and frequently consumed natural reward, and current observations have demonstrated homeostatic responses and neuroadaptations to sustained intermittent or chronic deprivation. Results obtained to date indicate that food deprivation affects glutamatergic synapses, favoring the insertion of GluA2-lacking α-Ammino-3-idrossi-5-Metil-4-idrossazol-Propionic Acid receptors (AMPARs) in postsynaptic membranes. Despite an increasing number of studies pointing towards specific changes in response to dietary restrictions in brain regions, such as the nucleus accumbens and hippocampus, none have investigated the long-term effects of such practice in the dorsal striatum. This basal ganglia nucleus is involved in habit formation and in eating behavior, especially that based on dopaminergic control of motivation for food in both humans and animals. Here, we explored whether we could retrieve long-term signs of changes in AMPARs subunit composition in dorsal striatal neurons of mice acutely deprived for 12 hours/day for two consecutive days by analyzing glutamatergic neurotransmission and the principal forms of dopamine and glutamate-dependent synaptic plasticity. Overall, our data show that a moderate food deprivation in experimental animals is a salient event mirrored by a series of neuroadaptations and suggest that dietary restriction may be determinant in shaping striatal synaptic plasticity in the physiological state.

Contemporary neurosciences have shown that emotion, thought and language involve the functioning of connected brain areas, which allow the recognition and expression of one���s own feelings. The present pilot study was aimed at investigating the link among verbal expression of emotional experiences (assessed through the Toronto Structured Interview for Alexithymia - TSIA), the capacity of emotional regulation (assessed by means of the Attachment Style Questionnaire, the Emotion Regulation Questionnaire, and the Coping Orientation to Problems Experiences), the linguistic structure and symbolic representation of narration (assessed through the Text Mining Analyses), and brain area structures (by means of a 3-T high-resolution structural Magnetic Resonance Imaging). To this aim, nine (males=5) healthy adult subjects were interviewed by means of the TSIA and scored on psychological questionnaires. The cortical and subcortical structural measures were also evaluated. TSIA transcripts were then analysed by using a cluster analysis and, subsequently, a correspondence analysis, and the values of lexical factors were correlated with cortical and subcortical structural measures as well as with TSIA and psychological scores. Overall, the reciprocal relationships among the measures of neurobiological structures, the capacity of identifying, describing and regulating emotions, and the ability of translating the emotional experiences into verbal forms, allowed to identify a complex pattern of biopsychosocial aspects, getting light on referential processes characterizing the verbally and not-verbally express emotions., Psychology Hub, Vol. 38 No. 2 (2021)

The acquisition of fear associative memory requires brain processes of coordinated neural activity within the amygdala, prefrontal cortex (PFC), hippocampus, thalamus and brainstem. After fear consolidation, a suppres- sion of fear memory in the absence of danger is crucial to permit adaptive coping behavior. Acquisition and maintenance of fear extinction critically depend on amygdala-PFC projections. The robust correspondence be- tween the brain networks encompassed cortical and subcortical hubs involved into fear processing in humans and in other species underscores the potential utility of comparing the modulation of brain circuitry in humans and animals, as a crucial step to inform the comprehension of fear mechanisms and the development of treat- ments for fear-related disorders. The present review is aimed at providing a comprehensive description of the literature on recent clinical and experimental researches regarding the noninvasive brain stimulation and optogenetics. These innovative manipulations applied over specific hubs of fear matrix during fear acquisition, consolidation, reconsolidation and extinction allow an accurate characterization of specific brain circuits and their peculiar interaction within the specific fear processing.

Fear extinction requires coordinated neural activity within the amygdala and medial prefrontal cortex (mPFC). Any behavior has a transcriptomic signature that is modified by environmental experiences, and specific genes are involved in functional plasticity and synaptic wiring during fear extinction. Here, we investigated the effects of optogenetic manipulations of prelimbic (PrL) pyramidal neurons on amygdala gene expression to analyze the specific transcriptional pathways involved in adaptive and maladaptive fear extinction. To this aim, transgenic mice were (or not) fear-conditioned and during the extinction phase they received optogenetic (or sham) stimulations over PrL pyramidal neurons. At the end of behavioral testing, electrophysiological (neural cellular excitability and Excitatory Post-Synaptic Currents) and morphological (spinogenesis) correlates were evaluated in the PrL pyramidal neurons. Furthermore, transcriptomic cell-specific RNA-analyses (differential gene expression profiling and functional enrichment analyses) were performed in amygdala pyramidal neurons. Our results show that the optogenetic activation of PrL pyramidal neurons in fear-conditioned mice induces fear extinction deficits, reflected in an increase of cellular excitability, excitatory neurotransmission, and spinogenesis of PrL pyramidal neurons, and in strong modifications of the transcriptome of amygdala pyramidal neurons. Understanding the electrophysiological, morphological and transcriptomic architecture of fear extinction may facilitate the comprehension of fear-related disorders.

Fear extinction requires coordinated neural activity within the amygdala and medial prefrontal cortex (mPFC). Any behavior has a transcriptomic signature that is modified by environmental experiences, and specific genes are involved in functional plasticity and synaptic wiring during fear extinction. Here, we investigated the effects of optogenetic manipulations of prelimbic (PrL) pyramidal neurons and amygdala gene expression to analyze the specific transcriptional pathways associated to adaptive and maladaptive fear extinction. To this aim, transgenic mice were (or not) fear-conditioned and during the extinction phase they received optogenetic (or sham) stimulations over photo-activable PrL pyramidal neurons. At the end of behavioral testing, electrophysiological (neural cellular excitability and Excitatory Post-Synaptic Currents) and morphological (spinogenesis) correlates were evaluated in the PrL pyramidal neurons. Furthermore, transcriptomic cell-specific RNA-analyses (differential gene expression profiling and functional enrichment analyses) were performed in amygdala pyramidal neurons. Our results show that the optogenetic activation of PrL pyramidal neurons in fear-conditioned mice induces fear extinction deficits, reflected in an increase of cellular excitability, excitatory neurotransmission, and spinogenesis of PrL pyramidal neurons, and associated to strong modifications of the transcriptome of amygdala pyramidal neurons. Understanding the electrophysiological, morphological, and transcriptomic architecture of fear extinction may facilitate the comprehension of fear-related disorders.

Background Approach system considered a motivational system that activates reward-seeking behavior is associated with exploration/impulsivity, whereas avoidance system considered an attentional system that promotes inhibition of appetitive responses is associated with active overt withdrawal. Approach and avoidance dispositions are modulated by distinct neurochemical profiles and synaptic patterns. However, the precise working of neurons and trafficking of molecules in the brain activity predisposing to approach and avoidance are yet unclear. Methods In 3 phenotypes of inbred mice, avoiding, balancing, and approaching mice, selected by using the Approach/Avoidance Y-maze, we analyzed endogenous brain levels of brain derived neurotrophic factor, one of the main secretory proteins with pleiotropic action. To verify the effects of the acute increase of brain derived neurotrophic factor, balancing and avoiding mice were bilaterally brain derived neurotrophic factor-infused in the cortical cerebellar regions. Results Approaching animals showed high levels of explorative behavior and response to novelty and exhibited higher brain derived neurotrophic factor levels in the cerebellar structures in comparison to the other 2 phenotypes of mice. Interestingly, brain derived neurotrophic factor-infused balancing and avoiding mice significantly increased their explorative behavior and response to novelty. Conclusions Cerebellar brain derived neurotrophic factor may play a role in explorative and novelty-seeking responses that sustain the approach predisposition.

Few investigations have analyzed the neuroanatomical substrate of empathic capacities in healthy subjects, and most of them have neglected the potential involvement of cerebellar structures. The main aim of the present study was to investigate the associations between bilateral cerebellar macro- and micro-structural measures and levels of cognitive and affective trait empathy (measured by Interpersonal Reactivity Index, IRI) in a sample of 70 healthy subjects of both sexes. We also estimated morphometric variations of cerebral Gray Matter structures, to ascertain whether the potential empathy-related peculiarities in cerebellar areas were accompanied by structural differences in other cerebral regions. At macro-structural level, the volumetric differences were analyzed by Voxel-Based Morphometry (VBM)- and Region of Interest (ROI)-based approaches, and at a micro-structural level, we analyzed Diffusion Tensor Imaging (DTI) data, focusing in particular on Mean Diffusivity and Fractional Anisotropy. Fantasy IRI-subscale was found to be positively associated with volumes in right cerebellar Crus 2 and pars triangularis of inferior frontal gyrus. The here described morphological variations of cerebellar Crus 2 and pars triangularis allow to extend the traditional cortico-centric view of cognitive empathy to the cerebellar regions and indicate that in empathizing with fictional characters the cerebellar and frontal areas are co-recruited.

To promote efficient explorative behaviors, subjects adaptively select spatial navigational strategies based on landmarks or a cognitive map. The hippocampus works alone or in conjunction with the dorsal striatum, both representing the neuronal underpinnings of the navigational strategies organized on the basis of different systems of spatial coordinate integration. The high expression of cannabinoid type 1 (CB1) receptors in structures related to spatial learning—such as the hippocampus, dorsal striatum and amygdala—renders the endocannabinoid system a critical target to study the balance between landmark- and cognitive map-based navigational strategies. In the present study, mice treated with the CB1-inverse agonist/antagonist AM251 or vehicle were trained on a Circular Hole Board, a task that could be solved through either navigational strategy. At the end of the behavioral testing, c-Fos immunoreactivity was evaluated in specific nuclei of the hippocampus, dorsal striatum and amygdala. AM251 treatment impaired spatial learning and modified the pattern of the performed navigational strategies as well as the c-Fos immunoreactivity in the hippocampus, dorsal striatum and amygdala. The present findings shed light on the involvement of CB1 receptors as part of the selection system of the navigational strategies implemented to efficiently solve the spatial problem.

Firing activity of external globus pallidus (GPe) is crucial for motor control and is severely perturbed in dys- tonia, a movement disorder characterized by involuntary, repetitive muscle contractions. Here, we show that GPe projection neurons exhibit a reduction of firing frequency and an irregular pattern in a DYT1 dystonia model. Optogenetic activation of the striatopallidal pathway fails to reset pacemaking activity of GPe neurons in mutant mice. Abnormal firing is paralleled by alterations in motor learning. We find that loss of dopamine D2 receptor-dependent inhibition causes increased GABA input at striatopallidal synapses, with subsequent downregulation of hyperpolarization-activated, cyclic nucleotide-gated cation (HCN) channels. Accordingly, enhancingin vivoHCN channel activity or blocking GABA release restores both the ability of striatopallidal inputs to pause ongoing GPe activity and motor coordination deficits. Our findings demonstrate an impaired striatopallidal connectivity, supporting the central role of GPe in motor control and, more importantly, iden- tifying potential pharmacological targets for dystonia.

The variance in the range of personality trait expression appears to be linked to structural variance in specific brain regions. In evidencing associations between personality factors and neurobiological measures, it seems evident that the cerebellum has not been up to now thought as having a key role in personality. This paper will review the most recent structural and functional neuroimaging literature that engages the cerebellum in personality traits, as novelty seeking and harm avoidance, and it will discuss the findings in the context of contemporary theories of affective and cognitive cerebellar function. By using region of interest (ROI)- and voxel-based approaches, we recently evidenced that the cerebellar volumes correlate positively with novelty seeking scores and negatively with harm avoidance scores. Subjects who search for new situations as a novelty seeker does (and a harm avoiding does not do) show a different engagement of their cerebellar circuitries in order to rapidly adapt to changing environments. The emerging model of cerebellar functionality may explain how the cerebellar abilities in planning, controlling, and putting into action the behavior are associated to normal or abnormal personality constructs. In this framework, it is worth reporting that increased cerebellar volumes are even associated with high scores in alexithymia, construct of personality characterized by impairment in cognitive, emotional, and affective processing. On such a basis, it seems necessary to go over the traditional cortico-centric view of personality constructs and to address the function of the cerebellar system in sustaining aspects of motivational network that characterizes the different temperamental traits.

Hypnotizability-the proneness to accept suggestions and behave accordingly-has a number of physiological and behavioral correlates (postural, visuomotor, and pain control) which suggest a possible involvement of cerebellar function and/or structure. The present study was aimed at investigating the association between cerebellar macro- or micro-structural variations (analyzed through a voxel-based morphometry and a diffusion tensor imaging approach) and hypnotic susceptibility. We also estimated morphometric variations of cerebral gray matter structures, to support current evidence of hypnotizability-related differences in some cerebral areas. High (highs, N = 12), and low (lows, N = 37) hypnotizable healthy participants (according to the Stanford Hypnotic Susceptibility Scale, form A) were submitted to a high field (3 T) magnetic resonance imaging protocol. In comparison to lows, highs showed smaller gray matter volumes in left cerebellar lobules IV/V and VI at uncorrected level, with the results in left lobule IV/V maintained also at corrected level. Highs showed also gray matter volumes smaller than lows in right inferior temporal gyrus, middle and superior orbitofrontal cortex, parahippocampal gyrus, and supramarginal parietal gyrus, as well as in left gyrus rectus, insula, and middle temporal cortex at uncorrected level. Results of right inferior temporal gyrus survived also at corrected level. Analyses on micro-structural data failed to reveal any significant association. The here found morphological variations allow to extend the traditional cortico-centric view of hypnotizability to the cerebellar regions, suggesting that cerebellar peculiarities may sustain hypnotizability-related differences in sensorimotor integration and emotional control.

Potentiating social, cognitive, and sensorimotor stimulations the Environmental Enrichment (EE) increases levels of novelty and complexity experienced by individuals. Growing evidence demonstrates that parental EE experience, even occurring in the pre-reproductive phase, affects behavioral and neural developmental trajectories of the offspring. To discover how the accumulation of early maternal complex experiences may inform and shape the social behavior of the following generation, we examined the effects of pre-reproductive enrichment of dams (post-natal days 21-72) on the play performances of their male and female adolescent offspring. Furthermore, we examined the effects of pre-reproductive enrichment on maternal behavior (during post-partum days 1-10) and male intruder aggression (on post-partum day 11). Since oxytocin modulates maternal care, social bonding, and agonistic behavior, the number of oxytocinergic neurons of the paraventricular (PVN) and supraoptic (SON) nuclei was examined in both dams and offspring. Results revealed that enriched females exhibited higher levels of pup-oriented behaviors, especially Crouching, and initiated pup-retrieval more quickly than standard females after the maternal aggression test. Such behavioral peculiarities were accompanied by increased levels of oxytocinergic neurons in PVN and SON. Moreover, pre-reproductive maternal EE cross-generationally influenced the offspring according to sex. Indeed, male pups born to enriched females exhibited a reduced play fighting associated with a higher number of oxytocinergic neurons in SON in comparison to male pups born to standard-housed females. In conclusion, pre-reproductive EE to the mothers affects their maternal care and has a cross-generational impact on the social behavior of their offspring that do not directly experiences EE. This article is part of the Special Issue entitled "Neurobiology of Environmental Enrichment".

The concept of “reserve” is defined as the resources being available to deal with adverse environmental influences on the human brain, and it has been proposed to account for the mismatch between brain pathology and clinical expression. New multidimensional approaches take into account the complexity and dynamic relation between the construct of reserve and post-damage neurobehavioral changes associated with negative consequences of neurological damage on functional outcomes, caregiver distress, and social reintegration following the traumatic event. In this framework, environmental factors, emotional aspects, and premorbid personality traits have increasingly been considered as potential moderators of traumatic brain damage . The present work constitutes a preliminary attempt to define and characterize the role of premorbid personality within the context of resilience against the detrimental effects of traumatic brain damage on adaptive functioning. Premorbid personality features appear to be a relevant factor of resilience that predicts brain recovery efficiency.

Personality traits are multidimensional traits comprising cognitive, emotional, and behavioral characteristics, and a wide array of cerebral structures mediate individual variability. Differences in personality traits covary with brain morphometry in specific brain regions. A cerebellar role in emotional and affective processing and on personality characteristics has been suggested. In a large sample of healthy subjects of both sexes and differently aged, the macro- and micro-structural variations of the cerebellum were correlated with the scores obtained in the Temperament and Character Inventory (TCI) by Cloninger. Cerebellar volumes were associated positively with Novelty Seeking scores and negatively with Harm Avoidance scores. Given the cerebellar contribution in personality traits and emotional processing, we investigated the cerebellar involvement even in alexithymia, construct of personality characterized by impairment in cognitive, emotional, and affective processing. Interestingly, the subjects with high alexithymic traits had larger volumes in the bilateral Crus 1. The cerebellar substrate for some personality dimensions extends the relationship between personality and brain areas to a structure up to now thought to be involved mainly in motor and cognitive functions, much less in emotional processes and even less in personality individual differences. The enlarged volumes of Crus 1 in novelty seekers and alexithymics support the tendency to action featuring both personality constructs. In fact, Novelty Seeking and alexithymia are rooted in behavior and inescapably have a strong action component, resulting in stronger responses in the structures more focused on action and embodiment, as the cerebellum is.

Although aversive memory has been mainly addressed by analysing the changes occurring in average populations, the study of neuronal mechanisms of outliers allows understanding the involvement of individual differences in fear conditioning and extinction. We recently developed an innovative experimental model of individual differences in approach and avoidance behaviors, classifying the mice as Approaching, Balancing or Avoiding animals according to their responses to conflicting stimuli. The approach and avoidance behaviors appear to be the primary reactions to rewarding and threatening stimuli and may represent predictors of vulnerability (or resilience) to fear. We submitted the three mice phenotypes to Contextual Fear Conditioning. In comparison to Balancing animals, Approaching and Avoiding mice exhibited no middle- or long-term fear extinction. The two non-extinguishing phenotypes exhibited potentiated glutamatergic neurotransmission (spontaneous excitatory postsynaptic currents/spinogenesis) of pyramidal neurons of medial prefrontal cortex and basolateral amygdala. Basing on the a priori individuation of outliers, we demonstrated that the maintenance of aversive memories is linked to increased spinogenesis and excitatory signaling in the amygdala-prefrontal cortex fear matrix.

Personality traits are multidimensional traits comprising cognitive, emotional, and behavioral characteristics, and a wide array of cerebral structures mediate individual variability. Differences in personality traits covary with brain morphometry in specific brain regions, and neuroimaging studies showed structural or functional abnormalities of cerebellum in subjects with personality disorders, suggesting a cerebellar role in affective processing and an effect on personality characteristics. To test the hypothesis that cerebellar [white matter (WM) and cortex] volumes are correlated with scores obtained in the four temperamental scales of the Temperament and Character Inventory (TCI) by Cloninger, a total of 125 healthy participants aged 18-67 years of both genders (males = 52) completed the TCI and underwent magnetic resonance imaging. The scores obtained in each temperamental scale were associated with the volumes of cerebellar WM and cortex of right and left hemispheres separately by using linear regression analyses. In line with our hypothesis, novelty seeking (NS) scores were positively associated with WM and cortex cerebellar volumes. Harm avoidance (HA) scores were negatively associated with WM and cortex cerebellar volumes. The range of individual differences in NS and HA scores reflects the range of variances of cerebellar volumes. The present data indicating a cerebellar substrate for some personality traits extend the relationship between personality and brain areas to a structure up to now thought to be involved mainly in motor and cognitive functions, much less in emotional processes and even less in personality individual differences. Hum Brain Mapp, 2012. © 2012 Wiley Periodicals, Inc. Language: en

The "cholinergic hypothesis" of dementia posits that the progressive loss of basal forebrain cholinergic neurons and the consequent decrease of acetylcholine levels in the deafferented projection sites are correlated with degree of cognitive decline in dementia. It has also been proposed that early dysfunction of the basal forebrain (BF) cholinergic system may be a risk factor for subsequent cognitive decline and possibly dementia. To characterize how age when BF cholinergic system is lesioned affects behavioral performances and morphology of neocortical neurons, seven-day-old rats were bilaterally i.c.v. injected with 192 IgG-saporin. In adulthood, these animals were subjected to spatial and associative tests. Subsequently, the morphology of parietal pyramidal neurons was assessed. The same behavioral and morphological evaluations were made in 80-day-old rats tested three weeks after bilateral i.c.v. injections of 192 IgG-saporin. The behavioral consequences of both cholinergic depletions were markedly similar. While both groups of lesioned animals exhibited very subtle deficits in the Morris water maze, they were significantly impaired in spatial discrimination in the open field and the radial maze. Paralleling behavioral data, the results of the morphological analysis revealed comparable increases in number and density of spines in apical and basal dendrites in layer-III parietal pyramidal neurons following both neonatal and adult cholinergic depletions. The present results demonstrate that the consequences of abnormal maturation of the cholinergic system are not substantially different from those evoked by cholinergic dysfunction in adulthood and provide a developmental psychobiological perspective of the neuronal foundations of the impaired cognitive functions.

The compensation that follows cerebellar lesions is based on synaptic modifications in many cortical and subcortical regions, although its cellular mechanisms are still unclear. Changes in glutamatergic receptor expression may represent the synaptic basis of the compensated state. We analyzed in rats the involvement of glutamatergic system of the cerebello-frontal network in the compensation following a right hemicerebellectomy. We evaluated motor performances, spatial competencies and molecular correlates in compensated hemicerebellectomized rats which in the frontal cortex contralateral to the hemicerebellectomy side received injections of anti-NMDA antibodies from patients affected by anti-NMDA encephalitis. In the compensated hemicerebellectomized rats, the frontal injections of anti-NMDA antibodies elicited a marked decompensation state characterized by slight worsening of the motor symptoms as well as severe impairment of spatial mnesic and procedural performances. Conversely, in the sham-operated group the frontal injections of anti-NMDA antibodies elicited slight motor and spatial impairment. The molecular analyses indicated that cerebellar compensatory processes were related to a relevant rearrangement of glutamatergic synapses (NMDA and AMPA receptors and other glutamatergic components) along the entire cortico-cerebellar network. The long-term maintenance of the rearranged glutamatergic activity plays a crucial role in the maintenance of recovered function.

Many different labels have been proposed over the years to cover the definition of approach and avoidance. Initially, an Approach-Avoidance distinction was conceptualized in terms of valence-based processes, rather than over behavior. In 1960s, an Approach-Withdrawal distinction was introduced arguing that in all organisms the motivation is grounded in overt behavioral actions toward or away from stimuli. Subsequently, it was presumed that action and emotional tendencies are grounded in specific brain systems. Only recently, it was preferred the Approach-Avoidance distinction that expands the previous Approach-Withdrawal distinction in terms of energization of the behavior by (motivation), or direction of the action toward (behavior), positive stimuli in the case of the approach, and in parallel, energization of the behavior by, or direction of the action away from, negative stimuli in the case of the avoidance (Laricchiuta and Petrosini, 2014). The approach and avoidance behaviors appear to be the primary reactions to novel, rewarding, or dangerous stimuli on which all successive responses are based in order to gain successful adaptation. Thus, the positive or negative valence of the stimulus is considered the core of Approach-Avoidance distinction. Further, the hedonic principle to approach pleasure and avoid pain is frequently presumed to be the fundamental principle upon which motivation is built (Cornwell et al., 2014). In this framework, the approach system is considered a motivational system that activates reward-seeking behavior associated with impulsivity/exploration, whereas the avoidance system is considered an attentional system that promotes appetitive response inhibition or active overt withdrawal. The approach and avoidance behaviors are biologically based and constitutionally ingrained, since all organisms are “pre-programmed” to approach or avoid particular classes of stimuli. Approach and avoidance behaviors are anchored to the brain networks implicated in action and reaction to salient stimuli and controlling cognitive and attentional functions, reward sensitivity and emotional expression. These networks involve cerebral nodes interconnected as prefrontal cortex, amygdala, hypothalamus, striatum and cerebellum. By acting on them the neurotrasmitter systems increase the intensity of appetitive or defensive motivation. In fact, individual differences in approach and avoidance behaviors might be modulated by normal variance at the level of functioning of different neurotransmitter systems, such as dopaminergic, serotoninergic, noradrenergic and endocannabinoid systems as well as many peptides such as corticotropin releasing hormone. Experimental findings collected over the years show how the genetic background may play a critical role in modulating aminergic and GABAergic neurotransmission in prefrontal-accumbal-amygdaloid system in response to different rewarding or aversive experiences. Further, important results highlight the modulatory role for genetic variability of the dopaminergic system in individual differences in action-valence interaction (Richter et al., 2014). Physiologically, human temperaments of approach and avoidance are viewed as instigators of propensity. They produce immediate cognitive, affective, and behavioral inclinations in response to stimuli and orient individuals across domains and situations in a consistent fashion. Although the action undoubtedly emerges directly from the temperamental proclivities, ultimate behavioral outcomes are often function of the integration among goal pursuit, self-regulation, and temperament traits. Also the motivational salience plays an important role in shaping behavior. Individuals regulate their emotions in a wide variety of ways. The aberrations in the elaboration of aversive or rewarding stimuli as well as defective coping strategies characterize many psychopathological disorders, as attention-deficit/hyperactivity disorders, depression and substance abuse on one hand, or anxiety and post-traumatic stress disorder on the other hand. Thus, individual differences in approach and avoidance may represent predictors of vulnerability (or resilience) to neuropsychiatric diseases. The present Research Topic deals with the hot issue of individual differences in emotional and motivational processing, attempting to clarify “what,” “how,” and “why” of human and animal approach and avoidance behaviors, emphasizing the link between neuronal pattern and behavioral expression (McNaughton and Corr, 2014). The Topic includes experimental and clinical researches on the individual differences focusing behavioral characterization, structural and neurochemical profiles, synaptic connections, and receptor expression of approach and avoidance (Andolina et al., 2015). The translational models included in the present Research Topic consider the neurobiological mechanisms that give rise to outliers in approach and avoidance behaviors (Galatzer-Levy et al., 2014). Using the central tendency that assumes population homogeneity potentially overlooks the individual differences that explain responses to positive or negative stimuli. Crucial findings indicate that the heterogeneous approach and avoidance responses may be informative for understanding both resilience and impaired coping strategy. Further, great importance has been given to the researches facing the clarification of diseases associated with inappropriate responses to aversive or rewarding situations. An interesting contribution to the Research Topic has been given from a literature revision on Parkinson's disease to understand whether neurobiological (dopaminergic dysfunction) and neuropsychological (executive function alteration) modifications due to Parkinson's disease are associated to changes in approach-avoidance related personality features (Costa and Caltagirone, 2015). Parkinson's disease patients may show approach-avoidance imbalance as documented by lower novelty-seeking and higher harm-avoidance temperamental traits. It has been also addressed the issue of whether some forms of emotional regulation are healthier than others by focusing on two commonly used strategies: cognitive reappraisal (changing the way one thinks about potentially emotion-eliciting events) and expressive suppression (changing the way one behaviorally responds to emotion-eliciting events) (Cutuli, 2014). Findings on individual differences have been reviewed showing that using cognitive reappraisal to regulate emotions is associated with healthier patterns of affect, social functioning, and well-being in comparison to using expressive suppression. Once more, brain structural basis and functional activation linked to the habitual use of cognitive reappraisal and expressive suppression are discussed in detail. Given the growing need for standardized paradigms (Markett et al., 2014) and self-report inventories measuring individual differences in approach and avoidance, a new questionnaire measuring the revised constructs of behavioral inhibition and activation systems and fight-flight-freezing system has evidenced that a functional genetic polymorphism on the arginine vasopressin receptor 1a gene is associated with individual differences in the behavioral inhibition dimensions (Reuter et al., 2015). Considered as a whole, the present Research Topic calls attention on individual differences related to approach and avoidance behaviors as resilience or risk factors to disease and inefficient coping strategies, in response to environmental challenges.

The cerebellum provides a computational system for timing, sequencing, and modeling aimed at the flexible manipulation of motor, cognitive and emotional processes. It may render such processes increasingly more efficient and adaptive, mainly in facing novelty-, observation- and flexibility-related behaviors, crucial features of creativity. Because of the large number of anatomo-functional connections between cerebellum and prefrontal cortex, it can be speculated that these areas interact in planning and organization, by permitting acquisition or imitation of new efficient competencies and by providing flexible shifting among already acquired and stored solutions. The cerebellum may teach the prefrontal cortex how to “think ahead,” predicting or anticipating functions inherent to creativity.

Approach and avoidance behaviors—the primary responses to the environmental stimuli of danger, novelty and reward—are associated with the brain structures that mediate cognitive functionality, reward sensitivity and emotional expression. Individual differences in approach and avoidance behaviors are modulated by the functioning of amygdaloid-hypothalamic-striatal and striatal-cerebellar networks implicated in action and reaction to salient stimuli. The nodes of these networks are strongly interconnected and by acting on them the endocannabinoid and dopaminergic systems increase the intensity of appetitive or defensive motivation. This review analyzes the approach and avoidance behaviors in humans and rodents, addresses neurobiological and neurochemical aspects of these behaviors, and proposes a possible synaptic plasticity mechanism, related to endocannabinoid-dependent long-term potentiation (LTP) and depression that allows responding to salient positive and negative stimuli.

Neuroimaging studies have indicated that people with alexithymia show structural and functional alterations in brain areas associated with emotional awareness, as amygdala, insula, anterior cingulate cortex, fusiform gyrus and parahippocampal gyrus, and only occasionally alterations in the cerebellar activity were reported. The main goal of the present study was to investigate the associations between gray and white matter cerebellar macro- (Voxel-Based Morphometry) and micro- (Mean Diffusivity and Fractional Anisotropy) structural measures (evaluated by means of a 3-T high-resolution structural Magnetic Resonance Imaging and a Diffusion Tensor Imaging scan protocol) and the presence of alexithymia (evaluated by means of 20-item Toronto Alexithymia Scale), in a sample of 60 healthy subjects having low, borderline or high alexithymia. As a corollary aim, the associations between volumes of amygdala, insula, anterior cingulate cortex, fusiform gyrus or parahippocampal gyrus and alexithymia scores have been investigated. Cerebellar gray matter volumes were positively associated with alexithymia scores. The subjects with high alexithymic traits had larger volumes in the bilateral Crus 1 in comparison to the remaining subjects. Volumes of right amygdala, left insula and left parahippocampal gyrus were negatively associated with the alexithymia scores. Thus, alexithymia scores were linked directly with cerebellar areas and inversely with limbic and para-limbic system, proposing a possible functional modality for the cerebellar involvement in emotional processing. The increased volumes in Crus 1 of subjects with high alexithymic traits may be related to an altered embodiment process leading to not-cognitively interpreted emotions.

Novelty Seeking (NS) and Harm Avoidance (HA) temperamental traits are related to approaching or avoiding motivational circuits relying on the integrity and functionality of distributed brain areas implicated in arousal and action. The present study verified whether and how macro- and micro-structural variations of basal ganglia are correlated with scores obtained in the NS and HA temperamental scales of the Temperament and Character Inventory by Cloninger. To this aim, 125 healthy adults aged 18-67 years of both sexes completed the Temperament and Character Inventory and underwent a high-resolution T1-weighted magnetic resonance imaging and a diffusion tensor imaging using a 3T scanner. The scores obtained in the temperamental scales were associated with volumes, mean diffusivity and fractional anisotropy measures of basal ganglia of both hemispheres separately, by using linear regression analyses. We found increased bilateral caudate and pallidum volumes associated with higher NS scores, as well as increased mean diffusivity in the bilateral putamen associated with higher HA scores. Macro- and micro-structural variations of basal ganglia regions contribute to explain the biological variance associated with NS or HA personality phenotype. The present findings evidencing some brain-temperament relationships highlight the importance of obtaining macro- and micro-structural measures in relation to individual differences.

In contextual fear conditioning animals have to integrate various elemental stimuli into a coherent representation of the condition and then associate context representation with punishment. Although several studies indicated the modulating role of endocannabinoid system (ECS) on the associative learning, ECS effect on contextual fear conditioning requires further investigations. The present study assessed the effects of the increased endocannabinoid anandamide (AEA) tone on acquisition, retrieval and extinction of the contextual fear conditioning. Given that AEA may bind to cannabinoid type 1 (CB1) receptors as well as to postsynaptic ionotropic Transient Receptor Potential Vanilloid type 1 (TRPV1) channels, particular attention was paid in determining how the increased AEA tone influenced fear responses. Furthermore, it was investigated how the ECS modulated the effects of stress-sensitization on fear response. Thus, mice submitted or not to a social defeat stress protocol were treated with drugs acting on ECS, CB1 receptors or TRPV1 channels and tested in a contextual fear conditioning whose conditioning, retrieval and extinction phases were analyzed. ECS activation influenced the extinction process and contrasted the stress effects on fear memory. Furthermore, CB1 receptor antagonist blocked and TRPV1 channel antagonist promoted short- and long-term extinction. The present study indicates that ECS controls the extinction of aversive memories in the contextual fear conditioning.

Background Systemic inflammation might cause neuronal damage and sustain neurodegenerative diseases and behavior impairment, with the participation of pro-inflammatory cytokines, like tumor necrosis factor (TNF)-α and interleukin (IL)-18. However, the potential contribution of these cytokines to behavioral impairment in the long-term period has not been fully investigated. Methods Wistar rats were treated with a single intraperitoneal injection of LPS (5 mg/kg) or vehicle. After 7 days and 10 months, the animal behavior was evaluated by testing specific cognitive functions, as mnesic, discriminative, and attentional functions, as well as anxiety levels. Contextually, TNF-α and IL-18 protein levels were measured by ELISA in defined brain regions (that is, frontal cortex, hippocampus, striatum, cerebellum, and hypothalamus). Results Behavioral testing demonstrated a specific and persistent cognitive impairment characterized by marked deficits in reacting to environment modifications, possibly linked to reduced motivational or attentional deficits. Concomitantly, LPS induced a TNF-α increase in the hippocampus and frontal cortex (from 7 days onward) and cerebellum (only at 10 months). Interestingly, LPS treatment enhanced IL-18 expression in these same areas only at 10 months after injection. Conclusions Overall, these results indicate that the chronic neuroinflammatory network elicited by systemic inflammation involves a persistent participation of TNF-α accompanied by a differently regulated contribution of IL-18. This leads to speculation that, though with still unclear mechanisms, both cytokines might take part in long-lasting modifications of brain functions, including behavioral alteration.

Approach or avoidance behaviors are accompanied by perceptual vigilance for, affective reactivity to and behavioral predisposition towards rewarding or punitive stimuli, respectively. We detected three subpopulations of C57BL/6J mice that responded with avoiding, balancing or approaching behaviors not induced by any experimental manipulation but spontaneously displayed in an approach/avoidance conflict task. Although the detailed neuronal mechanisms underlying the balancing between approach and avoidance are not fully clarified, there is growing evidence that endocannabinoid system (ECS) plays a critical role in the control of these balancing actions. The sensitivity of dorsal striatal synapses to the activation of cannabinoid CB1 receptors was investigated in the subpopulations of spontaneously avoiding, balancing or approaching mice. Avoiding animals displayed decreased control of CB1 receptors on GABAergic striatal transmission and in parallel increase of behavioral inhibition. Conversely, approaching animals exhibited increased control of CB1 receptors and in parallel increase of explorative behavior. Balancing animals reacted with balanced responses between approach and avoidance patterns. Treating avoiding animals with URB597 (fatty acid amide hydrolase inhibitor) or approaching animals with AM251 (CB1 receptor inverse agonist) reverted their respective behavioral and electrophysiological patterns. Therefore, enhanced or reduced CB1-mediated control on dorsal striatal transmission represents the synaptic hallmark of the approach or avoidance behavior, respectively. Thus, the opposite spontaneous responses to conflicting stimuli are modulated by a different involvement of endocannabinoid signaling of dorsal striatal neurons in the range of temperamental traits related to individual differences.

Cerebellar compensation is a reliable model of lesion-induced plasticity occurring through profound synaptic and neurochemical modifications in cortical and sub-cortical regions. As the recovery from cerebellar deficits progresses, the firstly enhanced glutamate striatal transmission is then normalized. The time course of cerebellar compensation and the concomitant striatal modifications might be influenced by protocols of environmental enrichment (EE) differently timed in respect to cerebellar lesion. In the present study, we analyzed the effects of different EE protocols on postural and locomotor behaviors (by means of a neurological rating scale), and on striatal synaptic activity (by means of recordings of spontaneous glutamate-mediated excitatory postsynaptic currents (sEPSCs)) and on morphological correlates (by means of density and dendritic length of Fast Spiking (FS) interneurons) following hemicerebellectomy (HCb) in rats. Cerebellar motor deficits were reduced faster in the enriched animals in comparison to standard housed HCbed rats. The beneficial influence of EE was higher in the animals enriched before the HCb than in rats enriched only after the lesion. In parallel, the HCb-induced increase in striatal sEPSCs was not observed in rats enriched before HCb and attenuated in rats enriched after HCb. Furthermore, the EE prevented the shrinkage of dendritic arborization of FS striatal interneurons. Also this effect was more marked in animals enriched before than after the HCb. The exposure to EE exerted either neuro-protective or therapeutic actions on the cerebellar deficits. The experience-dependent changes of the synaptic and neuronal connectivity observed in the striatal neurons may represent one of the mechanisms through which the enrichment facilitates functional compensation following the cerebellar damage.

The exposure to enriched environments allows the maintenance of normal cognitive functioning even in the presence of brain pathology. Up until now, clinical and experimental studies have investigated environmental effects mainly on the symptoms linked to the presence of neuro-degenerative diseases, and no study has yet analyzed whether prolonged exposure to complex environments allows modifying the clinical expression and compensation of deficits of cerebellar origin. In animals previously exposed to complex stimulations, the effects of cerebellar lesions have been analyzed to verify whether a prolonged and intense exposure to complex stimulations affected the compensation of motor and cognitive functions following a cerebellar lesion. Hemicerebellectomized or intact animals housed in enriched or standard conditions were administered spatial tests. Postural asymmetries and motor behavior were also assessed. Exposure to the enriched environment almost completely compensated the effects of the hemicerebellectomy. In fact, the motor and cognitive performances of the enriched hemicerebellectomized animals were similar to those of the intact animals. The plastic changes induced by enhanced mental and physical activity seem to provide the development of compensatory responses against the disrupting motor and cognitive consequences of the cerebellar damage.