This study assessed the effects of reversible lesions with microinfusions of the GABAA agonist muscimol (MUSC) to infralimbic cortex (IL; Brodmann’s area 25) of the medial prefrontal cortex (mPFC) on trace eyeblink conditioning and extinction in rabbits (Oryctolagus cuniculus). Four groups were tested: rabbits receiving MUSC infusions 5 min before acquisition and extinction sessions (MUSC/MUSC group), rabbits receiving vehicle (VEH) 5 min before acquisition and extinction sessions (VEH/VEH group), rabbits receiving MUSC before acquisition and VEH before extinction sessions (MUSC/VEH group), and rabbits receiving VEH before acquisition and MUSC before extinction sessions (VEH/MUSC). Results revealed that MUSC infusions to IL had no effects on acquisition but retarded extinction when injected before either acquisition or extinction sessions. These findings are among the first to demonstrate that MUSC infusions to the IL disrupt extinction of an EB CR in rabbits, and are in agreement with data from rodent studies noting the critical role of IL for the extinction of aversive fear-conditioned responses.
... The rodent infralimbic (IL) subregion of the medial prefrontal cortex has been shown to modulate the specificity and generalization attributes of cued and contextual fear memories at the acquisition stage: pre-training damage to the IL 11 or inactivation of both IL and prelimbic (PL) 12 was sufficient to produce memory overgeneralization. Similarly, lesioning or inactivating the IL before cued or contextual fear memory acquisition induced a relative resistance to extinction 11,13,14 . The IL has also been associated with aversive memory consolidation. ...
... Animals in which the IL was inactivated during consolidation extinguished similarly to controls within the session but were unable to recall the extinction memory the following day. This result is in line with that found when the IL was lesioned or inactivated before cued and contextual fear memory acquisition [12][13][14] , suggesting that the IL controls the formation of extinction-sensitive fear memories at both stages. Of note, activity in the IL similarly has a role not only after consolidation, in maintaining extinction-sensitive fear memories 47 , but also during their extinction acquisition and consolidation [48][49][50] . ...
Lesioning or inactivating the infralimbic (IL) subregion of the medial prefrontal cortex before acquisition produces more generalized and extinction-resistant fear memories. However, whether and how it modulates memory specificity and extinction susceptibility while consolidation takes place is still unknown. The present study aims to investigate these questions using muscimol-induced temporary inactivation and anisomycin-induced protein synthesis inhibition in the rat IL following contextual fear conditioning. Results indicate that the IL activity immediately after acquisition, but not six hours later, controls memory generalization over a week, regardless of its strength. Such IL function depends on the context-shock pairing since muscimol induced no changes in animals exposed to immediate shocks or the conditioning context only. Animals in which the IL was inactivated during consolidation extinguished similarly to controls within the session but were unable to recall the extinction memory the following day. Noteworthy, these post-acquisition IL inactivation-induced effects were not associated with changes in anxiety, as assessed in the elevated plus-maze test. Anisomycin results indicate that the IL protein synthesis during consolidation contributes more to producing extinction-sensitive fear memories than memory specificity. Collectively, present results provide evidence for the IL's role in controlling generalization and susceptibility to extinction during fear memory consolidation.
... Similarly, enhancing IL, but not PL, activity during tone-shock extinction training facilitates extinction acquisition and consolidation (Do-Monte et al., 2015;Thompson et al., 2010) and enhancing IL activity immediately following tone-shock extinction training facilitates consolidation (Do-Monte et al., 2010Thompson et al., 2010). Additionally, evidence supports that the IL is important for extinction learning when the CS and US are separated by a trace interval, as chemogenetic IL inhibition impairs the extinction of trace fear conditioning (Mukherjee and Caroni, 2018), and pharmacological IL inhibition via GABA A agonism impairs the extinction of trace eyeblink conditioning (Oswald et al., 2015). Taken together, a large body of evidence supports that IL activity is important for the extinction of learned associations with footshock stimuli. ...
NETT, K.E., and R.T. LaLumiere. Infralimbic cortex functioning across motivated behaviors: Can the differences be reconciled? NEUROSCI BIOBEHAV REV 21(1) XXX-XXX, 2021.-The rodent infralimbic cortex (IL) is implicated in higher order executive functions such as reward seeking and flexible decision making. However, the precise nature of its role in these processes is unclear. Early evidence indicated that the IL promotes the extinction and ongoing inhibition of fear conditioning and cocaine seeking. However, evidence spanning other behavioral domains, such as natural reward seeking and habit-based learning, suggests a more nuanced understanding of IL function. As techniques have advanced and more studies have examined IL function, identifying a unifying explanation for its behavioral function has become increasingly difficult. Here, we discuss evidence of IL function across motivated behaviors, including associative learning, drug seeking, natural reward seeking, and goal-directed versus habit-based behaviors, and emphasize how context-specific encoding and heterogeneous IL neuronal populations may underlie seemingly conflicting findings in the literature. Together, the evidence suggests that a major IL function is to facilitate the encoding and updating of contingencies between cues and behaviors to guide subsequent behaviors.
Previous studies have implicated 2 cortical regions interconnected with the hippocampal formation, the retrosplenial cortex (RSC) and the medial prefrontal cortex (mPFC), as loci important for the acquisition of hippocampally dependent trace eyeblink conditioning. These loci have also been proposed to serve as long-term storage sites of task critical information. This study used lesions made prior to training to investigate the roles of the RSC, as well as the caudal and rostral subdivisions of the mPFC, in the acquisition and subsequent extinction of trace eyeblink conditioning in the rabbit. The caudal mPFC and rostral mPFC were shown to be critical for acquisition and extinction of the conditioned reflex, respectively. The data indicate that the RSC is not critical for acquisition or extinction of the trace conditioned reflex.
Rabbits were eyeblink conditioned while their accessory abducens nucleus (ACC), facial nucleus (FN), and surrounding reticular formation (RF) were temporarily inactivated with microinjections of muscimol to determine whether these structures are critically involved in acquisition of the conditioned eyeblink response (CR). Rabbits performed no CRs or unconditioned responses (URs) during inactivation training. Training was continued without inactivation and rabbits performed the CR at asymptotic levels from the start of training without inactivation. They had fully learned the CR while their ACC, FN, and RF were inactivated, despite performing no CRs or URs at all during inactivation. These results rule out any critical role for neurons within the ACC, FN, or surrounding RF in acquisition of the classically conditioned eyeblink response.
The pattern of generalization following motor learning can provide a probe on the neural mechanisms underlying learning. For example, the breadth of generalization to untrained regions of space after visuomotor adaptation to targets in a restricted region of space has been attributed to the directional tuning properties of neurons in the motor system. Building on this idea, the effect of different types of perturbations on generalization (e.g., rotation vs. visual translation) have been attributed to the selection of differentially tuned populations. Overlooked in this discussion is consideration of how the context of the training environment may constrain generalization. Here, we explore the role of context by having participants learn a visuomotor rotation or a translational shift in two different contexts, one in which the array of targets were presented in a circular arrangement and the other in which they were presented in a rectilinear arrangement. The perturbation and environments were either consistent (e.g., rotation with circular arrangement) or inconsistent (e.g., rotation with rectilinear arrangement). The pattern of generalization across the workspace was much more dependent on the context of the environment than on the perturbation, with broad generalization for the rectilinear arrangement for both types of perturbations. Moreover, the generalization pattern for this context was evident, even when the perturbation was introduced in a gradual manner, precluding the use of an explicit strategy. We describe how current models of generalization might be modified to incorporate these results, building on the idea that context provides a strong bias for how the motor system infers the nature of the visuomotor perturbation and, in turn, how this information influences the pattern of generalization.
Delay eyeblink conditioning is established by paired presentations of a conditioned stimulus (CS) such as a tone or light and an unconditioned stimulus (US) that elicits eyelid closure before training. The CS and US inputs converge on Purkinje cells in the cerebellar cortex. The cerebellar cortex plays a substantial role in acquisition of delay eyeblink conditioning in rabbits and rodents, but the specific area of the cortex that is necessary for acquisition in rodents has not been identified. A recent study identified an eyeblink microzone in the mouse cerebellar cortex at the base of the primary fissure (Heiney, Kim, Augustine, & Medina, 2014). There is no evidence that the cortex in this eyeblink microzone plays a role in rodent eyeblink conditioning but it is a good candidate region. Experiment 1 examined the effects of unilateral (ipsilateral to the US) lesions of lobule HVI, the lateral anterior lobe, or the base of the primary fissure on eyeblink conditioning in rats. Lesions of either the anterior lobe or lobule HVI impaired acquisition, but lesions of the base of the primary fissure produced the largest deficit. Experiment 2 used reversible inactivation with muscimol to demonstrate that inactivation of the putative eyeblink microzone severely impaired acquisition and had only a modest effect on retention of eyeblink conditioning. The findings indicate that the base of the primary fissure is the critical zone of the cerebellar cortex for acquisition of eyeblink conditioning in rats.
Memories are acquired and encoded within large-scale neuronal networks spanning different brain areas. The anatomical and functional specificity of such long-range interactions and their role in learning is poorly understood. The amygdala and the medial prefrontal cortex (mPFC) are interconnected brain structures involved in the extinction of conditioned fear. Here, we show that a defined subpopulation of basal amygdala (BA) projection neurons targeting the prelimbic (PL) subdivision of mPFC is active during states of high fear, whereas BA neurons targeting the infralimbic (IL) subdivision are recruited, and exhibit cell-type-specific plasticity, during fear extinction. Pathway-specific optogenetic manipulations demonstrate that the activity balance between pathways is causally involved in fear extinction. Together, our findings demonstrate that, although intermingled locally, long-range connectivity defines distinct subpopulations of amygdala projection neurons and indicate that the formation of long-term extinction memories depends on the balance of activity between two defined amygdala-prefrontal pathways.
Retrieval of fear extinction memory is associated with increased firing of neurons in the medial prefrontal cortex (mPFC). It is unknown, however, how extinction learning-induced changes in mPFC activity are relayed to target structures in the amygdala, resulting in diminished fear responses. Here, we show that fear extinction decreases the efficacy of excitatory synaptic transmission in projections from the mPFC to the basolateral nucleus of the amygdala (BLA), whereas inhibitory responses are not altered. In contrast, synaptic strength at direct mPFC inputs to intercalated neurons remains unchanged after extinction. Moreover, priming stimulation of mPFC projections induced heterosynaptic inhibition in auditory cortical inputs to the BLA. These synaptic mechanisms could contribute to the encoding of extinction memory by diminishing the ability of projections from the mPFC to drive BLA activity while retaining the ability of intercalated neurons to inhibit the output nuclei of the amygdala.
