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Review
, 171 (20), 4556-74

Developmental Rodent Models of Fear and Anxiety: From Neurobiology to Pharmacology

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Review

Developmental Rodent Models of Fear and Anxiety: From Neurobiology to Pharmacology

Despina E Ganella et al. Br J Pharmacol.

Abstract

Anxiety disorders pose one of the biggest threats to mental health in the world, and they predominantly emerge early in life. However, research of anxiety disorders and fear-related memories during development has been largely neglected, and existing treatments have been developed based on adult models of anxiety. The present review describes animal models of anxiety disorders across development and what is currently known of their pharmacology. To summarize, the underlying mechanisms of intrinsic 'unlearned' fear are poorly understood, especially beyond the period of infancy. Models using 'learned' fear reveal that through development, rats exhibit a stress hyporesponsive period before postnatal day 10, where they paradoxically form odour-shock preferences, and then switch to more adult-like conditioned fear responses. Juvenile rats appear to forget these aversive associations more easily, as is observed with the phenomenon of infantile amnesia. Juvenile rats also undergo more robust extinction, until adolescence where they display increased resistance to extinction. Maturation of brain structures, such as the amygdala, prefrontal cortex and hippocampus, along with the different temporal recruitment and involvement of various neurotransmitter systems (including NMDA, GABA, corticosterone and opioids) are responsible for these developmental changes. Taken together, the studies described in this review highlight that there is a period early in development where rats appear to be more robust in overcoming adverse early life experience. We need to understand the fundamental pharmacological processes underlying anxiety early in life in order to take advantage of this period for the treatment of anxiety disorders.

Figures

Figure 1
Figure 1
Developmental time course of different forms of unlearned fear and the neurotransmitter systems known to be involved. Maternal separation induced ultrasonic vocalizations (USVs; orange line) rise gradually from birth and peak between postnatal days (P) 6–8 then gradually declines, and are modulated by a number of neurotransmitters including NMDA, GABA, corticotropin and serotonin. Predator odour-induced freezing (green line) is developmentally regulated, with a reduction in freezing with increasing age. Increase in GABA receptor or reduction of corticotropin receptor signalling have been shown to reduce this type of unlearned fear. The emergence of light-potentiated startle occurs at P17 and is observed throughout life, although its intensity across development has not yet been characterized. Antagonism of the glycine receptor or the injection of corticotropin-releasing hormone can also potentiate startle at this age.
Figure 2
Figure 2
Phases of fear conditioning and extinction. (A) Acquisition of conditioned fear is the increase in fear-conditioned response (CR) at each conditioned stimulus (CS) – unconditioned stimulus (US) trial during the conditioning session. This learning is consolidated to form a CS–US association. Well-consolidated conditioning memory is expressed as high levels of CR to the CS when tested at least 1 day after acquisition. Poor acquisition, a failure in consolidation, or spontaneous forgetting will lead to low levels of expression of CR to the CS at test. (B) Acquisition of extinction is the decrease in fear CR at each CS-alone trial during the extinction session. This learning consolidates to form an extinction memory. Good extinction expression is the low levels of fear to the extinguished CS when tested later. Poor extinction expression (because of changes in the external, internal, or temporal context or a failure in consolidation) will lead to high levels of CS-elicited fear at test.
Figure 3
Figure 3
Developmental time course of fear learning and extinction, and the known brain regions involved. Prior to postnatal day (P) 10, odour-shock pairings induce an odour-preference learning in rodents. This paradoxical odour-shock learning depends on the olfactory bulb and the locus coeruleus. Rodents older than P10 can learn conditioned fear to a discrete cue, with amygdala being a critical structure for life. However, fear expression or extinction do not require the medial prefrontal cortex (mPFC) until after 3 weeks of age. Following 3 weeks of life, the hippocampus is also involved and rats can learn context-fear associations, and fear extinction becomes context- and mPFC-dependent. Early adolescence (4–6 weeks of age) appears to be a unique maturation period during which fear expression and extinction are both temporarily impaired before recovery during adulthood.

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