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Summary A complex array of inhibitory interneurons tightly controls hippocampal activity, but how such diversity specifically affects memory processes is not well understood. We find that a small subclass of type 1 cannabinoid receptor (CB1R)-expressing hippocampal interneurons determines episodic-like memory consolidation by linking dopamine D1 receptor (D1R) signaling to GABAergic transmission. Mice lacking CB1Rs in D1-positive cells (D1-CB1-KO) display impairment in long-term, but not short-term, novel object recognition memory (NOR). Re-expression of CB1Rs in hippocampal D1R-positive cells rescues this NOR deficit. Learning induces an enhancement of in vivo hippocampal long-term potentiation (LTP), which is absent in mutant mice. CB1R-mediated NOR and the associated LTP facilitation involve local control of GABAergic inhibition in a D1-dependent manner. This study reveals that hippocampal CB1R-/D1R-expressing interneurons control NOR memory, identifying a mechanism linking the diversity of hippocampal interneurons to specific behavioral outcomes., Graphical Abstract, Highlights • CB1Rs are present in hippocampal D1R-positive interneurons • CB1R/D1R-positive interneurons control the late phase of recognition memory • CB1R/D1R-positive interneurons control learning-induced facilitation of LTP, Oliveira da Cruz et al. show that a specific subpopulation of hippocampal CB1 and D1 receptor-positive neurons controls late consolidation of recognition memory and associated synaptic plasticity by moderating local inhibitory GABAergic activity in the hippocampus.

Corticosteroid-mediated stress responses require the activation of complex brain circuits involving mitochondrial activity, but the underlying cellular and molecular mechanisms are scantly known. The endocannabinoid system is implicated in stress coping, and it can directly regulate brain mitochondrial functions via type 1 cannabinoid (CB1) receptors associated with mitochondrial membranes (mtCB1). In this study, we show that the impairing effect of corticosterone in the novel object recognition (NOR) task in mice requires mtCB1 receptors and the regulation of mitochondrial calcium levels in neurons. Different brain circuits are modulated by this mechanism to mediate the impact of corticosterone during specific phases of the task. Thus, whereas corticosterone recruits mtCB1 receptors in noradrenergic neurons to impair NOR consolidation, mtCB1 receptors in local hippocampal GABAergic interneurons are required to inhibit NOR retrieval. These data reveal unforeseen mechanisms mediating the effects of corticosteroids during different phases of NOR, involving mitochondrial calcium alterations in different brain circuits.

Previous evidence suggests that prenatal exposure to THC (pTHC) derails the neurodevelopmental trajectories towards a vulnerable phenotype for impaired emotional regulation and limbic memory. Here we aimed to investigate pTHC effect on hippocampus-related cognitive functions and markers of neuroplasticity in adolescent male offspring. Wistar rats were exposed to THC (2 mg/kg) from gestational day 5 to 20 and tested for spatial memory, object recognition memory and reversal learning in the reinforce-motivated Can test and in the aversion-driven Barnes maze test; locomotor activity and exploration, anxiety-like behaviour, and response to natural reward were assessed in the open field, elevated plus maze, and sucrose preference tests, respectively. The gene expression levels of NMDA NR1-2A subunits, mGluR5, and their respective scaffold proteins PSD95 and Homer1, as well as CB1R and the neuromodulatory protein HINT1, were measured in the hippocampus. pTHC offspring exhibited deficits in spatial and object recognition memory and reversal learning, increased locomotor activity, increased NR1-, decreased NR2A- and PSD95-, increased mGluR5- and Homer1-, and augmented CB1R- and HINT1-hippocampal mRNA levels. Our data shows that pTHC is associated with specific impairment in spatial cognitive processing and effectors of hippocampal neuroplasticity and suggests novel targets for future pharmacological challenges.

During adolescence, internal and external factors contribute to engaging with alcohol binge drinking (ABD), putting at risk the neurodevelopment of brain regions crucial for emotional control and stress coping. This research assessed the prevalence of ABD in late adolescent students of Southern Italy and characterized their psychological profile and drinking motives. Translational effects of alcohol binge drinking in the animal model were also studied. Seven hundred and fifty-nine high school students of both sexes (aged 18–20) were recruited. Alcohol Use Disorder Identification Test-Consumption (AUDIT-C), Drinking Motives Questionnaire-Revised Short Form, Millon Clinical Multiaxial Inventory-Third Ed., State-Trait Anxiety Inventory, Connor-Davidson Resilience Scale, and Basic Self-Esteem Scale identified alcohol habits, drinking motives, and psychopathological profile. Eighty-five percentage of the students drank alcohol and 28% of them engaged in ABD; AUDIT-C correlated with enhancement, coping, and conformity motives. ABD was related to a greater likelihood of presenting clinical syndromes and personality disorders, as well as low resilience and self-esteem. Thereafter, in the pre-clinical model, adolescent male rats were exposed to alcohol (3.5 g/kg) in an intermittent binge-like paradigm and tested during prolonged abstinence. Rats were evaluated for anxiety-like behavior, motivated behaviors, resilience, and stress response following a psychosocial challenge. Binge-like alcohol-exposed adolescent rats displayed high integrated z-score for social- and novelty-induced anxiety, altered motivation-driven output, decreased resilience, and a blunted HPA axis response to psychosocial stress, with respect to respective controls. Our data confirm that ABD is the chosen pattern of drinking in a significant percentage of high school students in Southern Italy, and highlights AUDIT-C score as a relevant parameter able to predict the occurrence of affective disturbances. The evidence from the preclinical model shows that ABD produces detrimental consequences in the adolescent rat brain, resulting in negative affect, emotional dysregulation, and aberrant stress response, pointing to decreasing excessive alcohol drinking as a primary goal for the global act for brain health.

Background Alcohol binge drinking may compromise the functioning of the nucleus accumbens (NAc), i.e. the neural hub for processing reward and aversive responses. Methods As socially stressful events pose particular challenges at developmental stages, this research applied the resident–intruder paradigm as a model of social stress, to highlight behavioural neuroendocrine and molecular maladaptive plasticity in rats at withdrawal from binge-like alcohol exposure in adolescence. In search of a rescue agent, cannabidiol (CBD) was selected due to its favourable effects on alcohol- and stress-related harms. Results Binge-like alcohol exposed intruder rats displayed a compromised defensive behaviour against the resident and a blunted response of the stress system, in addition to indexes of abnormal dopamine (DA)/glutamate plasticity and dysfunctional spine dynamics in the NAc. CBD administration (60 mg/kg) was able to: (1) increase social exploration in the binge-like alcohol exposed intruder rats, at the expenses of freezing time, and in control rats, which received less aggressive attacks from the resident; (2) reduce corticosterone levels independently on alcohol previous exposure; (3) restore DA transmission and (4) facilitate excitatory postsynaptic strength and remodelling. Conclusions Overall, the maladaptive behavioural and synaptic plasticity promoted by the intersection between binge-like alcohol withdrawal and exposure to adverse social stress can be rescued by a CBD détente effect that results in a successful defensive strategy, supported by a functional endocrine and synaptic plasticity. The current data highlight CBD's relevant therapeutic potential in alcohol- and stress-related harms, and prompt further investigation on its molecular targets.

In recent years, the mode of alcoholic intake known as binge drinking (BD) has become a common practice, especially among adolescents who, due to socio-environmental motives, tend to reach a rapid state of drunkenness. This drunkeness leads to alterations in brain areas responsible for executive functions and cognitive processes, as well as to the genesis of factors that predispose to lasting addiction. Likewise, nicotine leads to a comparable degree of addiction. On this basis, the aim of this research was to evaluate, on a cohort of 349 high school students (15–17 years old) in the province of Palermo, the following: (I) the drinking model of alcoholic beverages; (II) the use of nicotine and the degree of dependence; (III) the correlation between the consumption of alcoholic beverages and the use of nicotine. We employed the AUDIT-C test and the Fagerström test, two valid and standard instruments, in order to assess alcohol and nicotine use, respectively. Statistical analysis of the data showed that male and female students consumed alcohol prominently in a BD mode (77.2%, audit score (AS) 3.497, confidence interval (CI) 3.206–3.788; 69.6%, AS 2.793, CI 2.412–3.274) and nicotine (41.5%, Fagerström score (FS) 3.882, CI 3.519–4.245; 28%, FS 3.286, CI 2.547–4.024). Furthermore, a positive correlation between alcohol consumption and nicotine use was found for male (r = 0.6798, p < 0.0001) and female (r = 0.6572, p < 0.0001) students. This study provided further insights into the use of legal substances of abuse in adolescents, evidencing the obvious need for the promotion of specific school educational programs aimed at the wellbeing of youth populations.

Aim of the research was to investigate whether a temporal structure could be detected in the behavioural response to an aversive stimulation. A fear-related memory task was used in rats, placed in a modified version of the Novel Object Recognition task known as Emotional Object Recognition task, i.e. a behavioural assay that orbits around the declarative memory for an aversive experience. To this purpose, twelve male Wistar rats, divided in two groups (Control and Aversive memory), observed after 4 h (OR4h) and after 24 h (OR24h) from the delivery of an aversive stimulation, associated to a specific object, were used. Data were evaluated both in terms of conventional quantitative approaches and by means of T-pattern analysis, namely a multivariate technique able to unveil the temporal structure of behaviour and the relationships amongst the behavioural items in time. Results evidenced several changes between groups and over time as well. Mean occurrences and mean durations showed significant differences between OR4h and OR24h sessions and between Control and Aversive memory groups for behavioural items of Exploration, Object-related aversion and Immobility. T-pattern analysis revealed important changes of behavioural variability, complexity and repetitiveness, (i.e., the three main qualitative features of T-patterns) in the Aversive memory group. These outcomes highlight a simpler and linear behavioural profile, focused only on specific sequences of particularly repetitive events. Overall, the present study demonstrates a) the presence of a temporal organization of fear-related behavioural events and b) the influence of learning on the modifications observed over time.

Background:Cannabinoid consumption during pregnancy has been increasing on the wave of the broad-based legalisation of cannabis in Western countries, raising concern about the putative detrimental outcomes on foetal neurodevelopment. Indeed, since the endocannabinoid system regulates synaptic plasticity, emotional and cognitive processes from early stages of life interfering with it and other excitability endogenous modulators, such as neuropeptide Y (NPY), might contribute to the occurrence of a vulnerable phenotype later in life.Aims:This research investigated whether in utero exposure to Δ9-tetrahydrocannabinol (THC) may induce deficits in emotional/cognitive processes and alcohol vulnerability in adolescent offspring. NPY and excitatory postsynaptic density (PSD) machinery were measured as markers of neurobiological vulnerability.Methods:Following in utero THC exposure (2 mg/kg delivered subcutaneously), preadolescent male rat offspring were assessed for: behavioural reactivity in the open field test, neutral declarative memory and aversive limbic memory in the Novel Object and Emotional Object Recognition tests, immunofluorescence for NPY neurons and the PSD proteins Homer-1, 1b/c and 2 in the prefrontal cortex, amygdala and nucleus accumbens at adolescence (cohort 1); and instrumental learning, alcohol taking, relapse and conflict behaviour in the operant chamber throughout adolescence until early adulthood (cohort 2).Results:In utero THC-exposed adolescent rats showed: (a) increased locomotor activity; (b) no alteration in neutral declarative memory; (c) impaired aversive limbic memory; (d) decreased NPY-positive neurons in limbic regions; (e) region-specific variations in Homer-1, 1b/c and 2 immunoreactivity; (f) decreased instrumental learning and increased alcohol drinking, relapse and conflict behaviour in the operant chamber.Conclusion:Gestational THC impaired the formation of memory traces when integration between environmental encoding and emotional/motivational processing was required and promoted the development of alcohol-addictive behaviours. The abnormalities in NPY signalling and PSD make-up may represent the common neurobiological background, suggesting new targets for future research.

The perinatal window is a critical developmental time when abnormal gestational stimuli may alter the development of the stress system that, in turn, influences behavioral and physiological responses in the newborns. Individual differences in stress reactivity are also determined by variations in maternal care, resulting from environmental manipulations. Despite glucocorticoids are the primary programming factor for the offspring's stress response, therapeutic corticosteroids are commonly used during late gestation to prevent preterm negative outcomes, exposing the offspring to potentially aberrant stress reactivity later in life. Thus, in this study, we investigated the consequences of one daily s.c. injection of corticosterone (25 mg/kg), from gestational day (GD) 14-16, and its interaction with offspring early handling, consisting in a brief 15-min maternal separation until weaning, on: (i) maternal behavior; and (ii) behavioral reactivity, emotional state and depressive-like behavior in the adolescent offspring. Corticosterone plasma levels, under non-shock- and shock-induced conditions, were also assessed. Our results show that gestational exposure to corticosterone was associated with diminished maternal care, impaired behavioral reactivity, increased emotional state and depressive-like behavior in the offspring, associated with an aberrant corticosterone response. The early handling procedure, which resulted in increased maternal care, was able to counteract the detrimental effects induced by gestational corticosterone exposure both in the behavioral- and neurochemical parameters examined. These findings highlight the potentially detrimental consequences of targeting the stress system during pregnancy as a vulnerability factor for the occurrence of emotional and affective distress in the adolescent offspring. Maternal extra-care proves to be a protective strategy that confers resiliency and restores homeostasis.

While a lot is known about the mechanisms promoting aversive learning, the impact of rewarding factors on memory has received comparatively less attention. This research investigates reward-related explicit memory in male rats, by taking advantage of the emotional-object recognition test. This is based on the prior association, during conditioned learning, between a rewarding experience (the encounter with a receptive female rat) and an object; afterwards rat discrimination and recognition of the â emotional objectâ is recorded in the presence of a novel object, as a measure of positive limbic memory formation. Since endocannabinoids are critical for processing reward and motivation, the consequences of the stimulation of cannabinoid signalling are also assessed by the administration of WIN 55,212-2 at pre- and post-conditioning time. Our results show that rats encode the association between object and rewarding experience, form positive limbic memory of the emotional object, and retrieve this information in the face of novelty. Stimulation of the cannabinoid system at pre-conditioning time is able to strengthen reward-related explicit memory in the presence of novelty, whereas post-conditioning activation increases approach behaviour to novel stimuli. The assessment of limbic memory by the emotional-object recognition test can help unveiling the addictive and confounding properties of psychotropic drugs.

The past two decades of data derived from addicted individuals and preclinical animal models of addiction implicate a role for the excitatory glutamatergic transmission within the mesolimbic structures in alcoholism. The cellular localization of the glutamatergic receptor subtypes, as well as their signaling efficiency and function, are highly dependent upon discrete functional constituents of the postsynaptic density, including the Homer family of scaffolding proteins. The consequences of repeated alcohol administration on the expression of the Homer family proteins demonstrate a crucial and active role, particularly for the expression of Homer2 isoform, in regulating alcohol-induced behavioral and cellular neuroplasticity. The interaction between Homer2 and alcohol can be defined as a mutual relation: alcohol consumption enhances the expression of Homer2 protein isoform within the nucleus accumbens and the extended amygdala, cerebral areas where, in turn, Homer2 is able to mediate the development of the “pro-alcoholic” behavioral phenotype, as a consequence of the morpho-functional synaptic adaptations. Such findings are relevant for the detection of the strategic molecular components that prompt alcohol-induced functional and behavioral disarrangement as targets for future innovative treatment options.

Newborn babies who need intensive medical care are often sheltered into a special area of the hospital called Neonatal Intensive Care Unit (NICU). In this structure, babies are regularly subject to conditions that would be considered harmful by older children and adults. In the last years, many clinical researches have paid particular attention to effectiveness of various pharmacological therapies, regularly used in neonatal intensive care that have sharply reduced mortality of newborn and preterm infants. Although there are many classes of drugs used for the treatment of different diseases (sepsis, pain, seizures, pulmonary hypertension and infection), the fledgling population is more difficult to handle because there are many physiological changes that happen in infants which do not occur at any other time of life. Furthermore, there are many drugs used during the first stage of life, able to induce various toxic effects on the principal organs and apparatus. For example, there are many relationships between amikacina serum levels and central conduction time in brainstem auditory evoked potentials within therapeutic range levels in newborns as index of drug toxicity in brainstem auditory centers in neonatally exposed infants. In this chapter, we will focus mainly on the principal pharmacological strategies used for dealing with neonatal diseases in the Neonatal Intensive Care Unit.