Carlos M. Coelho

The brain-specific microRNA miR-128b regulates the formation of fear-extinction memory

MicroRNAs are small non-coding RNAs that mediate post-transcriptional gene silencing. Fear-extinction learning in C57/Bl6J mice led to increased expression of the brain-specific microRNA miR-128b, which disrupted stability of several plasticity-related target genes and regulated formation of fear-extinction memory. Increased miR-128b activity may therefore facilitate the transition from retrieval of the original fear memory toward the formation of a new fear-extinction memory.

p300/CBP-associated factor selectively regulates the extinction of conditioned fear

It is well established that the activity of chromatin-modifying enzymes is crucial for regulating gene expression associated with hippocampal-dependent memories. However, very little is known about how these epigenetic mechanisms influence the formation of cortically dependent memory, particularly when there is competition between opposing memory traces, such as that which occurs during the acquisition and extinction of conditioned fear. Here we demonstrate, in C57BL/6 mice, that the activity of p300/CBP-associated factor (PCAF) within the infralimbic prefrontal cortex is required for long-term potentiation and is necessary for the formation of memory associated with fear extinction, but not for fear acquisition. Further, systemic administration of the PCAF activator SPV106 enhances memory for fear extinction and prevents fear renewal. The selective influence of PCAF on fear extinction is mediated, in part, by a transient recruitment of the repressive transcription factor ATF4 to the promoter of the immediate early gene zif268, which competitively inhibits its expression. Thus, within the context of fear extinction, PCAF functions as a transcriptional coactivator, which may facilitate the formation of memory for fear extinction by interfering with reconsolidation of the original memory trace.

Paradoxical enhancement of fear extinction memory and synaptic plasticity by inhibition of the histone acetyltransferase p300

It is well established that the coordinated regulation of activity-dependent gene expression by the histone acetyltransferase (HAT) family of transcriptional coactivators is crucial for the formation of contextual fear and spatial memory, and for hippocampal synaptic plasticity. However, no studies have examined the role of this epigenetic mechanism within the infralimbic prefrontal cortex (ILPFC), an area of the brain that is essential for the formation and consolidation of fear extinction memory. Here we report that a postextinction training infusion of a combined p300/CBP inhibitor (Lys-CoA-Tat), directly into the ILPFC, enhances fear extinction memory in mice. Our results also demonstrate that the HAT p300 is highly expressed within pyramidal neurons of the ILPFC and that the small-molecule p300-specific inhibitor (C646) infused into the ILPFC immediately after weak extinction training enhances the consolidation of fear extinction memory. C646 infused 6 h after extinction had no effect on fear extinction memory, nor did an immediate postextinction training infusion into the prelimbic prefrontal cortex. Consistent with the behavioral findings, inhibition of p300 activity within the ILPFC facilitated long-term potentiation (LTP) under stimulation conditions that do not evoke long-lasting LTP. These data suggest that one function of p300 activity within the ILPFC is to constrain synaptic plasticity, and that a reduction in the function of this HAT is required for the formation of fear extinction memory.

The use of virtual reality in acrophobia research and treatment.

Acrophobia, or fear of heights, is a widespread and debilitating anxiety disorder affecting perhaps 1 in 20 adults. Virtual reality (VR) technology has been used in the psychological treatment of acrophobia since 1995, and has come to dominate the treatment of numerous anxiety disorders. It is now known that virtual reality exposure therapy (VRET) regimens are highly effective for acrophobia treatment. This paper reviews current theoretical understanding of acrophobia as well as the evolution of its common treatments from the traditional exposure therapies to the most recent virtually guided ones. In particular, the review focuses on recent innovations in the use of VR technology and discusses the benefits it may offer for examining the underlying causes of the disorder, allowing for the systematic assessment of interrelated factors such as the visual, vestibular and postural control systems.

The origins of specific phobias: Influential theories and current perspectives

Fears are quick and adaptive responses that permit powerful reply to imminent threats. Less adaptive, phobias are extreme manifestations of fear to objects or situations in the absence of a proportional danger. Although the utility of fear is accepted, the nature of phobias is controversial. Initial theories favored a fear conditioning-based explanation, with vicarious and information learning pathways subsequently included as additional routes to the development of specific phobias. More recently, an important group of investigations strengthened the case for a nonassociative account of fear acquisition proposing that evolutionarily relevant fears can occur without any need of critical learning experiences. In parallel, there is some evidence for a dedicated fear module in the detection of threats, involving the amygdala, which is relatively independent from conscious cognitive control. Nonetheless, cognitive models stress learning and developmental factors and their role in the etiology and maintenance of phobic behavior. This article critically reviews each of these views and theories stressing their recent developments, weaknesses, and controversies with an aim to provide the groundwork for the construction of a more integrated position. Finally, the authors suggest encouraging trends in recent research.

Deconstructing acrophobia: physiological and psychological precursors to developing a fear of heights.

Background: Acrophobia is one of the most prevalent phobias, affecting as many as 1 in 20 individuals. Of course, heights often evoke fear in the general population too, and this suggests that acrophobia might actually represent the hypersensitive manifestation of an everyday, rational fear. In this study, we assessed the role of sensory and cognitive variables in Acrophobia. Methods: Forty‐five participants (Mean age 25.07 years, 71% female) were assessed using a booklet with self‐reports as well as several behavioral measures. The data analysis consisted in multivariate linear regression using fear of heights as the outcome variable. Results: The regression analyses found that visual field dependence (measured with the rod and frame test), postural control (measured with the Sharpened Romberg Test), space and motion discomfort (measured with the Situational Characteristics Questionnaire), and bodily symptoms (measured with the Bodily Sensation Questionnaire) all serve as strong predictors for fear of heights (Adjusted r2=.697, P<.0001). Trait anxiety (measured with the State Trait Anxiety Inventory Form Y‐2) was not related with fear of heights, suggesting that this higher order vulnerability factor is not necessary for explaining this particular specific phobia in a large number of individuals. Conclusion: The findings reveal that fear of heights is an expression of a largely sensory phenomena, which can produce strong feelings of discomfort and fear in the otherwise calm individuals. We propose a theory that embraces all these factors and provides new insight into the aetiology and treatment of this prevalent and debilitating fear. Depression and Anxiety, 2010.

Visuo-vestibular contributions to anxiety and fear

The interactive roles of the visual and vestibular systems allow for postural control within boundaries of perceived safety. In specific circumstances, visual vestibular and postural interactions act as a cue that trigger fear, similarly to what occurs in motion sickness. Unusual patterns of visuo-vestibular interaction that emerge without warning can elicit fear, which can then become associated to a certain stimuli or situation, creating a CS-US association, (i.e., phobia), or can emerge without warning but also without becoming associated to a particular concomitant event (i.e., panic). Depending on the individual sensitivity to visuo-vestibular unusual patterns and its impact in postural control, individuals will be more or less vulnerable to develop these disorders. As such, the mechanism we here propose is also sufficient to explain the lack of certain fears albeit exposure. Following this rationale, a new subcategory of anxiety disorders, named visuo-vestibular fears can be considered. This model brings important implications for developmental and evolutionary psychological science, and invites to place visuo-vestibular fears in a particular subtype or specification within the DSM-5 diagnostic criteria.

The use of healthcare services for mental health problems by middle-aged and older adults

Although mental disorders occur commonly in later life, it has been reported that older adults are reluctant to seek help for their mental health problems. The purpose of this research study was to analyze the contact with healthcare professionals, self-perceived mental health problems and unmet needs, as reported by a nationally representative sample of community-dwelling adults. We report a cross-sectional analysis of all the respondents of the Australian National Survey of Mental Health and Wellbeing aged 55 years and older (N=3178). Results indicated that 306 (9.6%) participants had a DSM-IV classifiable mental disorder based on self-identified symptoms over the preceding 12 months. Of these, 146 (48%) reported that they had not consulted a healthcare professional to deal with their mental health problems. Among those who consulted with a healthcare professional, the general practitioner was the main point of contact. Medication and psychotherapy/counseling were the most frequent form of help obtained. Informational and instrumental help, such as help to sort out practical problems and to look after oneself, were the most reported unmet needs. These results suggest a gap in the provision of healthcare services for mental health problems directed toward the specific needs of aging adults. The reported unmet needs might be met by increasing awareness amongst healthcare professionals regarding mental health problems in later stages of life and by improving the access of older people to the services commonly provided by multidisciplinary teams.

Specific phobias in older adults: characteristics and differential diagnosis

BACKGROUND Differential diagnosis implies identifying shared and divergent characteristics between clinical states. Clinical work with older adults demands not only the knowledge of nosological features associated with differential diagnosis, but also recognition of idiosyncratic factors associated with this population. Several factors can interfere with an accurate diagnosis of specific phobia in older cohorts. The goal of this paper is to review criteria for specific phobia and its differential diagnosis with panic disorder, agoraphobia, post-traumatic stress disorder and obsessive compulsive disorder, while stressing the specific factors associated with aging. METHODS A literature search regarding specific phobia in older adults was carried out using PubMed. Relevant articles were selected and scanned for further pertinent references. In addition, relevant references related to differential diagnosis and assessment were used. RESULTS Etiologic factors, specificity of feared stimulus or situation, fear predictability and the nature of phobic situations are key points to be assessed when implementing a differential diagnosis of specific phobia. CONCLUSIONS First, age-related sensory impairments are common and interfere both with information processing and communication. Second, medical illnesses create symptoms that might cause, interfere with, or mimic anxiety. Third, cohort effects might result in underreporting, through the inability to communicate or recognize anxiety symptoms, misattributing them to physical conditions. Finally, diagnostic criteria and screening instruments were usually developed using younger samples and are therefore not adapted to the functional and behavioral characteristics of older samples.

MK-801-induced behavioural sensitisation alters dopamine release and turnover in rat prefrontal cortex

RationaleRepeated exposure to psychostimulants that either increase dopamine (DA) release or target N-methyl-d-aspartate (NMDA) receptors can induce behavioural sensitisation, a phenomenon that may be important for the processes of addiction and even psychosis. A critical component of behavioural sensitisation is an increase in DA release within mesocorticolimbic circuits. In particular, sensitisation to amphetamine leads to increased DA release within well-known sub-cortical brain regions and also regulatory regions such as prefrontal cortex (PFC). However, it is unknown how DA release within the PFC of animals is altered by sensitisation to NMDA receptor antagonists.ObjectivesThe aims of the present study were twofold, firstly to examine whether a single dose of dizocilpine maleate (MK-801) could induce long-term behavioural sensitisation and secondly to examine DA release in the PFC of sensitised rats.Materials and methodsBehavioural sensitisation was assessed by measuring locomotion after drug exposure. DA release in the PFC was measured using freely moving microdialysis.ResultsWe show that a single dose of MK-801 can induce sensitisation to subsequent MK-801 exposure in a high percentage of rats (66 %). Furthermore, rats sensitised to MK-801 have altered DA release and turnover in the PFC compared with non-sensitised rats.ConclusionSchizophrenia patients have been postulated to have ‘endogenous sensitisation’ to psychostimulants. MK-801-induced sensitised rats, in particular when compared with non-sensitised rats, provide a useful model for studying PFC dysfunction in schizophrenia.