Deletion of Stk11 and Fos in mouse BLA projection neurons alters intrinsic excitability and impairs formation of long-term aversive memory

Abstract

Conditioned taste aversion (CTA) is a form of one-trial learning dependent on basolateral amygdala projection neurons (BLApn). Its underlying cellular and molecular mechanisms remain poorly understood. RNAseq from BLApn identified changes in multiple candidate learning-related transcripts including the expected immediate early gene Fos and Stk11, a master kinase of the AMP-related kinase pathway with important roles in growth, metabolism and development, but not previously implicated in learning. Deletion of Stk11 in BLApn blocked memory prior to training, but not following it and increased neuronal excitability. Conversely, BLApn had reduced excitability following CTA. BLApn knockout of a second learning-related gene, Fos, also increased excitability and impaired learning. Independently increasing BLApn excitability chemogenetically during CTA also impaired memory. STK11 and C-FOS activation were independent of one another. These data suggest key roles for Stk11 and Fos in CTA long-term memory formation, dependent at least partly through convergent action on BLApn intrinsic excitability.

Perturbation of amygdala-cortical projections reduces ensemble coherence of palatability coding in gustatory cortex

“…Previous studies have reported robust effects of similar perturbations on palatabilityguided behavior (CTA learning and taste neophobia; Gallo et al, 1992;Lin et al, 2009;Lin and Reilly, 2012;Lavi et al, 2018;Levitan et al, 2020). In our hands, however, the impact of BLAGCx was less complete, and some GC neurons even gained palatability responses in perturbed trials (Figure 8B).…”

“…Palatability-relatedness in the firing of some single neurons was not utterly eliminated by our input manipulation; in some cases it was even enhanced. This fact is perhaps somewhat surprising given the well-known importance of amygdala for emotion processing (e.g., Quirk et al, 1995;Schoenbaum et al, 1998;LeDoux, 2000;Wang et al, 2005;Wassum and Izquierdo, 2015;Beyeler et al, 2018), and findings suggesting that BLA-GC circuitry is vital for palatability-related behavior (CTA learning and taste neophobia; Gallo et al, 1992;Lin and Reilly, 2012;Levitan et al, 2020). Our recent data suggest a possible explanation, however: as previously discussed, the emergence of Late-epoch palatability coding is revealed, using single-trial analyses involving Hidden Markov Modeling (HMM), to be a sudden transition into a new ensemble state, in which firing-rate changes occur simultaneously in multiple GC neurons (Jones et al, 2007;Miller and Katz, 2010;Sadacca et al, 2016); it is this sudden transition itself that directly drives behavior (Mukherjee et al, 2019).…”

Perturbation of amygdala-cortical projections reduces ensemble coherence of palatability coding in gustatory cortex

“…This fact is perhaps somewhat surprising given the well-known importance of amygdala for emotion processing (e.g. Quirk et al, 1995 ; Schoenbaum et al, 1998 ; LeDoux, 2000 ; Wang et al, 2005 ; Wassum and Izquierdo, 2015 ; Beyeler et al, 2018 ), and findings suggesting that BLA-GC circuitry is vital for palatability-related behavior (CTA learning and taste neophobia; Gallo et al, 1992 ; Lin and Reilly, 2012 ; Levitan et al, 2020 ). Our recent data suggest a possible explanation, however: as previously discussed, the emergence of Late-epoch palatability coding is revealed, using single-trial analyses involving Hidden Markov Modeling (HMM), to be a sudden transition into a new ensemble state, in which firing-rate changes occur simultaneously in multiple GC neurons ( Jones et al, 2007 ; Miller and Katz, 2010 ; Sadacca et al, 2016 ); it is this sudden transition itself that directly drives behavior ( Mukherjee et al, 2019 ).…”

“…Previous studies have reported robust effects of similar perturbations on palatability-guided behavior (CTA learning and taste neophobia; Gallo et al, 1992 ; Lin et al, 2009 ; Lin and Reilly, 2012 ; Lavi et al, 2018 ; Levitan et al, 2020 ). In our hands, however, the impact of BLA→GCx was less complete, and some GC neurons even gained palatability responses in perturbed trials ( Figure 8B ).…”

Loss of Stk11 in basolateral amygdalar projection neurons impairs taste aversion learning by altering the temporal pattern of taste response plasticity in gustatory cortex

“…This final state of the taste response is uniquely altered by conditioned taste aversion (CTA) – a powerful one-trial learning paradigm in which a taste becomes aversive after association with gastric malaise – a process requiring coordination between GC and basolateral amygdala (BLA). Previously, we found that one key requirement for learning in this circuit is expression of the serine/threonine kinase 11 (Stk11) gene (a tumor suppression gene which has only recently been associated with learning; Levitan et al, 2020). When Stk11 is knocked out in BLA projection neurons (BLApn), CTA learning fails to occur.…”