Past experience shapes the neural circuits recruited for future learning

Abstract

Experimental research controls for past experience, yet prior experience influences how we learn. Here, we tested whether we could recruit a neural population that usually encodes rewards to encode aversive events. Specifically, we found that GABAergic neurons in the lateral hypothalamus (LH) were not involved in learning about fear in naïve rats. However, if these rats had prior experience with rewards, LH GABAergic neurons became important for learning about fear. Interestingly, inhibition of these neurons paradoxically enhanced learning about neutral sensory information, regardless of prior experience, suggesting that LH GABAergic neurons normally oppose learning about irrelevant information. These experiments suggest that prior experience shapes the neural circuits recruited for future learning in a highly specific manner, reopening the neural boundaries we have drawn for learning of particular types of information from work in naïve subjects.

Full text

Articles
https://doi.org/10.1038/s41593-020-00791-4
1Department of Psychology, University of California, Los Angeles, Los Angeles, CA, USA. 2National Institute on Drug Abuse, Intramural Program, Baltimore,
MD, USA. ✉e-mail: melissa.j.sharpe@psych.ucla.edu; geoffrey.schoenbaum@nih.gov
Prior experience shapes the way we view our world. War mov-
ies are rife with veterans jumping at the sound of a car door
slamming when they return home, and lottery winners may
view life through rose-tinted glasses. We use our prior experience to
build models of our environment, and preferentially interpret new
experiences in a manner consistent with these models1–3. Despite
this, experimental research often does not consider a role for prior
experience as a factor. Research involving the human population
samples from homogeneous groups, controlling factors that might
give rise to differences. And of course, one of the main benefits of
animal research is an ability to eliminate prior experience. Rats and
mice, and to a lesser extent primates, used for experimental research
are housed in experiential vacuums, devoid of any exposure to
events that may contaminate their naïvety.
The few paradigms that investigated prior experience as an
experimental variable focused on extreme cases, where humans
or other animals are exposed to traumatic events4–7. Here, prior
trauma appears to ‘prime’ fear circuits to learn, resulting in indi-
viduals who have experienced trauma learning about an aversive
event so mild that others would usually ignore it4,5,8. This work is
integral to understanding some of the factors that could contrib-
ute to pathological fear, such as that seen in post-traumatic stress
disorder (PTSD). But what if these impacts can occur outside of a
pathological environment?
Here, we focused on GABAergic neurons in the LH, which
are generally implicated in learning about rewards9–13, to test
whether nonaversive experiences might prime other circuits to
encode fear memories. We found that LH GABAergic neurons
were important for encoding fear memories, but only in rats that
had experience with reward learning. Interestingly, reward learn-
ing did not recruit LH GABAergic neurons to encode all types of
learning; inhibiting these neurons while rats learned about cue–
cue relationships paradoxically enhanced such learning, regard-
less of whether the rats had experience with reward learning. This
suggests that these neurons oppose the development of associa-
tions between cues regardless of prior experience, biasing learning
towards rewards, but that they can be recruited to learn about other
motivationally relevant events, like aversive events, with appropriate
prior experience.
Results
Experiment 1: GABAergic neurons in the LH are not necessary to
learn about aversive events in naïve rats. Before training, all rats
underwent surgery to infuse virus and implant fiber optics targeting
the LH (Fig. 1 and Extended Data Fig. 1). We infused a Cre-dependent
adeno-associated virus (AAV) carrying halorhodopsin (NpHR)
(AAV5-EF1α-DIO-eNpHR3.0-eYFP; NpHR experimental group;
n = 4) or the control AAV vector (AAV5-EF1α-DIO-eYFP; eYFP
control group; n = 4) fused to enhanced yellow fluorescent protein
into the LH of rats expressing Cre recombinase from the glutamate
decarboxylase 1 (GAD1) promoter—one of two genes encoding the
GAD enzyme that converts glutamate to GABA (hereafter referred
to a GAD-Cre rats)10. During this surgery, we also implanted optic
fibers terminating 0.5 mm above the injection site in the LH, allow-
ing us to silence GABAergic neurons in the LH by delivering green
light (532 nm and 16 mW).
During conditioning, rats received three tone-shock pairings,
with an intertrial interval (ITI) varying around a 7-min mean. A
10-s auditory tone (70 dB) was presented followed by a 1-s foot
shock (0.5 mA), after a 1-s delay. Light was delivered into the brain
during the tone, beginning 500 ms before tone onset, and continu-
ing until 500 ms after tone offset. During this conditioning, all rats
learned to fear the tone stimulus, exhibiting an increase in freezing
elicited by the tone, with no difference between groups (Fig. 2a; trial:
F2,12 = 5.812, P = 0.017; trial × group: F2,12 = 0.187, P = 0.831; group:
F1,6 = 0.377, P = 0.562). There were no differences in levels of freez-
ing exhibited to the background contextual cues before cue pre-
sentation (mean (s.e.m.): eYFP, 45% (22.17%); NpHR, 35% (15%);
F1,6 = 0.140, P = 0.722). Following conditioning, we tested whether
inactivation of LH GABAergic neurons during conditioning would
impact freezing the following day. To test this, rats were presented
with the tone again without shock or light delivery into the LH. Rats
exhibited high levels of fear in response to the tone, and the level of
freezing did not differ between groups (Fig. 2b; group: F1,6 = 0.206,
Past experience shapes the neural circuits
recruited for future learning
Melissa J. Sharpe 1 ✉ , Hannah M. Batchelor2, Lauren E. Mueller2, Matthew P. H. Gardner2 and
Geoffrey Schoenbaum 2 ✉
Experimental research controls for past experience, yet prior experience influences how we learn. Here, we tested whether we
could recruit a neural population that usually encodes rewards to encode aversive events. Specifically, we found that GABAergic
neurons in the lateral hypothalamus (LH) were not involved in learning about fear in naïve rats. However, if these rats had prior
experience with rewards, LH GABAergic neurons became important for learning about fear. Interestingly, inhibition of these
neurons paradoxically enhanced learning about neutral sensory information, regardless of prior experience, suggesting that LH
GABAergic neurons normally oppose learning about irrelevant information. These experiments suggest that prior experience
shapes the neural circuits recruited for future learning in a highly specific manner, reopening the neural boundaries we have
drawn for learning of particular types of information from work in naïve subjects.
NATURE NEUROSCIENCE | VOL 24 | MARCH 2021 | 391–400 | www.nature.com/natureneuroscience 391
Content courtesy of Springer Nature, terms of use apply. Rights reserved