Translating Fear

Aug. 1, 2019
Analogous circuitry for fear acquisition and extinction between rodents and primates.

Analogous circuitry for fear acquisition and extinction between rodents and primates. In rodent models, connections between the basal nucleus (B, also referred to as the basolateral nucleus or BLA) and infralimbic cortex (IL) are thought to mediate fear extinction while basal to prelimbic (PL) connections mediate fear acquisition and retrieval (expression of fear). In the monkey, area 25/14c is thought to be homologous to the rodent IL and 24/32 to the rodent PL. Connections from the amygdala to these regions originate in both the monkey basal nucleus (B) and the accessory basal nucleus (AB), which both project to both areas 25/14c (sgACC) and areas 24/32 (pgACC). A subset of these neurons express collateral projections to sgACC and pgACC. Line thickness in the “primate” panels denotes relative projection density from the AB or Bi as detailed in this report. This is the putative circuitry in the non-human primate that may parallel fear learning circuitry in rodents. Findings denote both similarities and interesting differences to the current rodent model. 24: Brodmann Area 24. 25: Brodmann Area 25. AB: accessory basal nucleus of the amygdala. B: basal nucleus of the amygdala. IL: infralimbic cortex. LA: lateral nucleus of the amygdala. PL: prelimbic cortex.

Fear is a normal emotion in animals and humans alike, enabling us to stay safe and avoid harm.  Human anxiety disorders, including conditions such as post-traumatic stress disorder and social anxiety disorder, are conceptualized as an ‘over-reactivity’ of normal fear responses, or inability to modulate fear once the response is no longer appropriate. In the last decade, studies have delineated fear circuitry in rodents, to build models of how normal fear responses are instantiated when threat is present, and how fear learning is ‘neutralized’ by new learning when threat is no longer present (a process known as extinction).

In the rodent model, the amygdala and its connections to the prefrontal cortex (PFC) form two separate paths mediating fear learning and fear ‘extinction’, respectively. Cells in the basal nucleus of the amygdala are interconnected with the prelimbic PFC, and are required for fear instantiation. In contrast, neighboring cells in the basal nucleus project to the infralimbic PFC, which lays just beneath the prelimbic region in the PFC, and mediate fear extinction.  Thus, there is a reciprocal, and opposite, function of two closely embedded amygdala paths to the PFC. The model has raised hopes of possibly targeting circuits that modulate excessive anxiety, or weak fear extinction processes, in human psychiatric anxiety disorders.

Up until now, these models had not yet been examined in brains similar to those in humans. Nonhuman primates have brains that are like humans', not only because of their larger size, but also because of specializations of many brain regions that have evolved to support primate survival. In a new study, published in Cerebral Cortex, researchers at the University of Rochester Medical Center used very small, paired injections of neuronal tracers in the brains of nonhuman primates, and examined how the amygdala communicates with the primate analogues of the prelimbic (fear) and infralimbic (extinction) PFC.

The study, co-led by Keshov Sharma, a third year MSTP graduate student, found that, as in rodent, projections from the basal nucleus of the amygdala exist in nonhuman primates. However, there is also a substantial input from a neighboring region known as accessory basal nucleus, a greatly expanded amygdala nucleus in nonhuman primates and humans. This latter region actually provides relative greater input to the infralimbic (extinction) region of the PFC than the well-known basal nucleus. Moreover, they found that a subset of cells in the basal and accessory basal amygdala nuclei project to both the infralimbic and prelimbic PFC. This suggests that there is a contingent of amygdala neurons dedicated to ‘balancing’ responsivity between the two regions, which may allow the individual to flexibly track when threat is increasing or decreasing. 

In summary, this work shows that there a relatively understudied amygdala region, which is highly developed in primates, that plays a major role in proposed fear/extinction circuits in primates. Moreover, there is an amygdala circuit mechanism that allows simultaneous communication with both PFC nodes, suggesting ways in which the two circuits modulate one another. A key takeaway from the anatomic data is that cortical nodes of the primate ‘fear/extinction path’ are modulated by a balance of inputs from two amygdala sites (rather than one), and originate in some of the same neurons in both regions. This more nuanced picture, indicates that there is likely not a simple fear/extinction separation, and that in fact, the relative contribution from each amygdala region to these nodes may be a ‘target’ to better understand the development and treatment of fear disorders.

This research was funded by the National Institute of Mental Health and was conducted in the lab of Dr. Julie Fudge, an associate professor at the Del Monte Institute for Neuroscience. Additional authors include Emily Kelly, Charles Pfeifer, and Dr. Fudge.