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. Author manuscript; available in PMC: 2015 Apr 30.
Published in final edited form as: Curr Dir Psychol Sci. 2013 Apr 1;22(2):146–151. doi: 10.1177/0963721412471323

“Altered Fear in Mice and Humans”

Siobhan S Pattwell 1,*, BJ Casey 2, Francis S Lee 1,3
PMCID: PMC4415656  NIHMSID: NIHMS627908  PMID: 25937708

Abstract

Fear learning is an adaptive, evolutionarily conserved process that allows us to respond appropriately to threats in the environment. These threats can vary across different contexts (e.g., a lion in your yard versus a lion in a zoo) and by age (e.g., a dentist viewed by a child before cavities versus by an adult after cavities). Using the high degree of neural and behavioral conservation across species in fear regulation and the underlying neural circuitry, we examined how fear learning changes across contexts and development, focusing specifically on the environmentally changing and challenging period of adolescence. We show two surprising developmental findings specific to adolescents relative to older and younger ages: 1) diminished fear to previously aversive contexts; and 2) heightened fear to previously aversive cues. These behavioral changes are paralleled by developmental changes in frontolimbic circuitry. We discuss how these evolutionarily conserved mechanisms may be essential to survival of the species with the changing environmental demands (social, sexual and physical) of adolescence. Our findings also have important implications for unremitting forms of fear at the very core of anxiety related disorders that peak during the period of adolescence and when, during development, specific treatments for these disorders may be most effective.

Keywords: Adolescence, Fear, Mouse, Human, Amygdala, Hippocampus, Prefrontal Cortex, Development

INTRODUCTION

Throughout our lives, we experience fear. Children often fear the dark or imaginary monsters hiding under the bed. Teenagers may fear social rejection and humiliation, Adults may fear for their jobs or for their family's well being. These examples suggest that fear persists across the lifespan, but takes various forms as the environmental demands change in each developmental phase of life. This paper highlights how our response to and regulation of fear varies with age, especially during adolescence. We discuss how these changes may be adaptive or maladaptive depending on the changing demands of the environment.

By definition, adolescence poses new environmental challenges and potential threats, as the individual moves from dependence on parents to relative independence. As such, the adolescent must rapidly adapt to new social, sexual, and intellectual challenges. In parallel, with these changes are reported increases in the prevalence of anxiety and stress-related disorders affecting as many a 10% of our youth (Kessler et al., 2005; Merikangas et al., 2010; Newman et al., 1996). These health statistics highlight the importance of understanding how fear-related behavior and brain circuitry at the core of these disorders are changing during this period.

FEAR LEARNING AND MEMORY

Under normal circumstances, fear learning is a highly adaptive, evolutionarily conserved process that allows one to respond appropriately to threats in the environment. However, when fear persists long after the removal of any threat is when fear is often referred to as being pathological. This unremitting form of fear is a core component of many anxiety and stress-related disorders, affecting nearly 20% of Americans, or 40 million people and contributing to the country's near $58 billion in annual mental healthcare expenses (AHRQ/NIMH, 2006; Merikangas et al., 2011). Too often scientists trying to discover novel diagnostics and treatments for psychiatric disorders quickly jump into examining model systems of abberant behavior without a true understanding of the typical development of the core behavior and underlying neural circuitry. The large portion of youth represented in the US health statistics underscores the need to understand anxiety from a neurodevelopmental perspective. Specifically, what are the core behaviors underlying anxiety? How do they develop? What are their neurobiological bases and when does this development go awry?

Our work has attempted to address these questions by: 1) examining periods of typical developmental transition when these disorders have been shown to peak, such as the transition into and out of puberty; and 2) using translational developmental neuroscience to understand how behavior is translated across species. These two approaches require the use of behavioral paradigms that can be used both across development and species. Fear learning paradigms are advantageous, in this regard, as they can be used to assess fear learning equivalently in humans and rodents and across development. Moreover, because there is a high degree of neural and behavioral conservation across species in fear learning and fear circuitry (LeDoux, 2000), we have the added opportunity of delineating mechanisms of change in nonhuman species that would be more difficult to ascertain in humans.

In our experiments we have used a Pavlovian fear conditioning paradigm to directly examine how responses to threat change during the period of adolescence (Pattwell et al., 2012). Specifically we wanted to examine how the ability to regulate fear develops, once the threat of fear is removed (i.e., extinction learning). Classical (Pavlovian) conditioning involves pairing an inherently threatening and/or unpleasant stimulus (unconditioned stimulus-US), such as an electric shock or aversive noise, with a neutral stimulus such as a light flicker or tone (conditioned stimulus -CS). Through multiple pairings of the CS with the US, an association is formed such that the CS becomes predictive of the US. Eventually, after the CS-US association has been learned, presentations of the CS alone are capable of eliciting a fear response similar to that to the US. This conditioned response (CR) is often characterized physiologically by changes in autonomic arousal and behavior in humans through measuring changes in perspiration via skin conductance response (SCR), or in the case of the rodent, by freezing behavior. Acquisition and expression of a fear response, in both mice and humans, involves the amygdala, a subcortical structure within the temporal lobe implicated in emotional processing (Milad & Quirk, 2012)

Once a CS-US association has been formed, the CR can then be extinguished by giving multiple presentations of the CS alone, in the absence of the US. The initial CS-US pairing is not forgotten during the extinction process, as the fear almost always returns after standard extinction training with renewal, reinstatement, or the passage of time (Bouton, Westbrook, Corcoran, & Maren, 2006). Extinction learning, not to be confused with the process of mere forgetting, is an inhibitory process during which the relationship and expectancy of the CSUS pairing is modified (Sotres-Bayon & Quirk, 2010). By presenting the CS repeatedly, in the absence of any US, one can reevaluate the predictably of the CS, thus learning that a stimulus that was once associated with threat has become safe.

Extinction learning is mediated by the infralimbic cortex in rodents and the ventromedial prefrontal cortex in humans (Milad & Quirk, 2012; Phelps, Delgado, Nearing, & LeDoux, 2004). Uncovering the mechanisms involved in the development of fear acquisition, and extinction in particular, has wide clinical implications, as the most common and validated treatment for anxiety disorders involves exposure-based cognitive behavioral therapy. This treatment consists of identification of what triggers the anxiety followed by desensitization to it with repeated exposures, building directly upon the principles of extinction (Rothbaum & Davis, 2003). Strong cross-species preservation of the neural circuitry implicated in fear extinction learning is supported by human and nonhuman animal studies, further bolstering the translational credibility of rodent models for studying fear regulation and extinction (Gottfried & Dolan, 2004). We present evidence from two forms of fear conditioning- cued fear and contextual fear learning. These studies highlight changes in fear regulation and extinction and their neural correlates across development.

Cue Fear Extinction Learning

In parallel behavioral experiments across development in human children, adolescents, adults and mice on postnatal days (P)23, P29, P70 we examined cued fear learning and extinction. Previous studies in rodents have shown that cued fear acquisition is intact across all ages (McCallum, Kim, & Richardson, 2010). In human work, fear acquisition has been shown to be intact in adolescents and adults, but diminished in adolescents when using social cues (facial expression) as the unconditioned stimulus (Lau et al., 2011). In our own work in both mice and humans, using behavioral paradigms with nonsocial cues (tones or colored squares) across childhood, adolescence and adulthood, we show all ages successfully acquire conditioned cue fear memory equally well (Pattwell et al., 2012). Surprisingly, after the initial cue fear memory has been acquired, adolescents show attenuated fear extinction behavior compared to younger and older ages (See Figure 1). This diminished extinction learning during adolescence is observed in both humans and rodents (McCallum, et al., 2010; Pattwell, et al., 2012). Exploiting the mouse model system to further characterize the neural circuitry via electrophysiology and immunohistochemistry revealed blunted responses in ventromedial prefrontal subregions during extinction learning in the adolescent mice compared to younger and older mice. Together these findings suggest that fear regulation does not increase with age, but rather reflects a deflection (nonlinear change) in both behavior and the underlying neural circuitry in adolescents that is not observed in younger or older ages.

Figure 1. Cued fear extinction learning across development in mice and humans.

Figure 1

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(A) Behavioral paradigms for parallel fear conditioning experiments in humans and mice. (B) Analysis of extinction indices [(Averaged first two extinction trials) – (Averaged last two extinction trials)] reveals a main effect of age group for humans, such that adolescents display attenuated fear extinction learning compared to children and adults, [adolescent .05916 ± 0.06904; children .25435 ± 0.04839; adults 0. 22510 ± 0.05931). (C) A lack of extinction learning and retention of extinction memory is observed in adolescent mice, as displayed by a significantly decreased differential extinction indices [(Day 1, Tone 1) – (Day 4, Tone 5)] compared to older and younger ages, [(P23 66.5% ± 2.75; P29 14.72% ± 4.79; P70 35.17% ± 4.89). Adapted from Figure 1 of Pattwell et al., submitted.

Contextual Fear Learning

In addition to exploring fear learning to discrete stimuli using cued fear conditioning, our laboratories also have examined fear learning to discrete contexts using contextual fear conditioning (Pattwell, Bath, Casey, Ninan, & Lee, 2011). Unlike fear responses to discrete cues, which involve projections between the sensory thalamus, amygdala, and prefrontal cortex, fear responses to one's context integrate spatial aspects of the surrounding environment (Maren, 2011). The hippocampus, through its projections to the amygdala and prefrontal cortex, mediates fear responses based on safe vs. threatening environments. When mice are fear conditioned in a given context and subsequently returned to the conditioning context at later time points, they exhibit a fear response (freezing) to the conditioning context alone, in the absence of any tone cues.

To explore contextual fear across development, mice were fear conditioned at pre-adolescent, adolescent, and adult ages and tested the following day for contextual fear (See Figure 2). As expected, adult mice showed an increased freezing response upon being returned to the context in which they had previously been shocked (Pattwell, et al., 2011). Interestingly, pre-adolescent mice showed contextual fear responses that were indistinguishable from adult mice. Adolescent mice, however, showed a lack of contextual fear when returned to the conditioned context (Pattwell, et al., 2011). When the same adolescent mice were re-tested for contextual fear at later, post-adolescent time points, contextual fear expression emerged, suggesting that the expression of contextual fear was merely temporarily suppressed during the transition into and out of adolescence. This suppression of contextual fear expression during adolescence is associated with altered molecular signaling in the hippocampus and blunted activity in the basal nucleus of the amygdala, which receives hippocampal inputs during contextual conditioning. It may not be surprising that this temporary suppression of contextual fear expression coincides with the developmental period of adolescence when animals engage in heightened exploratory behavior required for sexual reproduction and survival (Spear & Brake, 1983). For an adolescent to exhibit heightened levels of contextual fear during this period of exploration may prove maladaptive. Specifically, they may be less willing to leave the safety of their parents’ niche and explore new environments. Importantly however, memory for threatening environments remain intact and are capable of being retrieved in adulthood when the animal must find a safe environment for itself and offspring.

Figure 2. Hippocampal-dependent contextual fear memory across adolescent development.

Figure 2

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(A) Mice of all ages were fear conditioned (fear cond) with three tone-shock pairings. Twenty-four hr later, they were returned to the conditioning context (Context A) and freezing behavior was scored. (B) Adolescent mice (P29 – P39) froze significantly less than both younger (P23 – P27) and older (P49 – P70) mice. All results are presented as a mean ± SEM. determined from analysis of 7-10 mice per group, (*p < 0.05, ***p < 0.001). Adapted from Figure 1, Pattwell et al., 2011.

DISCUSSION

Together, our studies suggest that the development of cued fear extinction and contextual fear expression occur in a nonlinear progression with adolescents showing diminished abilities relative to preadolescents and adults (Casey et al., 2008, 2010). This pattern of behavior may be adaptive in that the only way the adolescent can transition from dependence on the parent to relative independence is to explore new habitats in which to find new sources of food and mates. If the animal is afraid to venture out of the home environment, then it may exploit and deplete food in the home environment and fail to find a mate. However, if the animal ventures out and is attacked by a predator, the animal is no more likely to procreate or survive than if it had stayed at home. Thus, the animal needs to be highly vigilant to cues of threat in these new environments, which may explain the heightened fear response to cues of threat.

The study of fear learning and memory has garnered significant interest in recent years for its potential role in anxiety and stress-related disorders (LeDoux, 2000). Regulating fear is a principle component of these disorders. By studying the neural circuitry of fear learning and memories, insight can be gained into not only how these systems function normally across development, but also how they may go awry in the case of adolescent psychiatric disorders. By taking into account various developmental, environmental, and genetic factors, the hope is that insights may be gained toward finding better treatments and preventative measures for specific vulnerable populations. Specifically, our studies suggest that extinction learning is attenuated during the transition into and out of adolescence. Exposure therapy, which relies heavily on basic principles of extinction learning, may yield inadequate treatment responses if administered to adolescent patients. Likewise, if contextual fear expression is suppressed during adolescence, but contextual memories are encoded and expressed at later, post-adolescent time points, tapping into more contextual elements of fears may be a useful treatment approach. By highlighting developmental changes in the brain and behavior underlying fear learning, we seek to gain a better understanding of both normative and aberrant behaviors, which would otherwise be masked when thinking of neural development as a unidirectional, rigid process.

ACKNOWLEDGEMENTS

This work was supported by the Sackler Institute (B.J.C., S.S.P.); the DeWitt-Wallace Fund of the New York Community Trust (F.S.L.); National Institutes of Health Grants HD055177 (B.J.C. and S.S.P.) and MH079513 (B.J.C. and F.S.L.).

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