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1. Models of heterogeneous dopamine signaling in an insect learning and memory center

   https://doi.org/10.1371/journal.pcbi.1009205  

   Jiang, Linnie; Litwin-Kumar, Ashok (August 2021, PLOS Computational Biology)

   Morrison, Abigail (Ed.)

   The Drosophila mushroom body exhibits dopamine dependent synaptic plasticity that underlies the acquisition of associative memories. Recordings of dopamine neurons in this system have identified signals related to external reinforcement such as reward and punishment. However, other factors including locomotion, novelty, reward expectation, and internal state have also recently been shown to modulate dopamine neurons. This heterogeneity is at odds with typical modeling approaches in which these neurons are assumed to encode a global, scalar error signal. How is dopamine dependent plasticity coordinated in the presence of such heterogeneity? We develop a modeling approach that infers a pattern of dopamine activity sufficient to solve defined behavioral tasks, given architectural constraints informed by knowledge of mushroom body circuitry. Model dopamine neurons exhibit diverse tuning to task parameters while nonetheless producing coherent learned behaviors. Notably, reward prediction error emerges as a mode of population activity distributed across these neurons. Our results provide a mechanistic framework that accounts for the heterogeneity of dopamine activity during learning and behavior. 

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2. Temporal evolution of cortical ensembles promoting remote memory retrieval

   DeNardo, L.A.; Liu, C.D.; Allen, WE; Adams, EL; Friedmann, D; Fu, L.; Guenthner, CJ; Tessier-Lavigne, M; Luo, L. (April 2019, Nature Neuroscience)

   Memories of fearful events can last a lifetime. The prelimbic (PL) cortex, a subregion of prefrontal cortex, plays a critical role in fear memory retrieval over time. Most studies have focused on acquisition, consolidation, and retrieval of recent memories, but much less is known about the neural mechanisms of remote memory. Using a new knock-in mouse for activity-dependent genetic labeling (TRAP2), we demonstrate that neuronal ensembles in the PL cortex are dynamic. PL neurons TRAPed during later memory retrievals are more likely to be reactivated and make larger behavioral contributions to remote memory retrieval compared to those TRAPed during learning or early memory retrieval. PL activity during learning is required to initiate this time-dependent reorganization in PL ensembles underlying memory retrieval. Finally, while neurons TRAPed during earlier and later retrievals have similar broad projections throughout the brain, PL neurons TRAPed later have a stronger functional recruitment of cortical targets. 

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3. FosGFP expression does not capture a sensory learning-related engram in superficial layers of mouse barrel cortex

   https://doi.org/10.1073/pnas.2112212118  

   Lee, Jiseok; Urban-Ciecko, Joanna; Park, Eunsol; Zhu, Mo; Myal, Stephanie E.; Margolis, David J.; Barth, Alison L. (December 2021, Proceedings of the National Academy of Sciences)

   Immediate-early gene (IEG) expression has been used to identify small neural ensembles linked to a particular experience, based on the principle that a selective subset of activated neurons will encode specific memories or behavioral responses. The majority of these studies have focused on “engrams” in higher-order brain areas where more abstract or convergent sensory information is represented, such as the hippocampus, prefrontal cortex, or amygdala. In primary sensory cortex, IEG expression can label neurons that are responsive to specific sensory stimuli, but experience-dependent shaping of neural ensembles marked by IEG expression has not been demonstrated. Here, we use a fosGFP transgenic mouse to longitudinally monitor in vivo expression of the activity-dependent gene c-fos in superficial layers (L2/3) of primary somatosensory cortex (S1) during a whisker-dependent learning task. We find that sensory association training does not detectably alter fosGFP expression in L2/3 neurons. Although training broadly enhances thalamocortical synaptic strength in pyramidal neurons, we find that synapses onto fosGFP+ neurons are not selectively increased by training; rather, synaptic strengthening is concentrated in fosGFP− neurons. Taken together, these data indicate that expression of the IEG reporter fosGFP does not facilitate identification of a learning-specific engram in L2/3 in barrel cortex during whisker-dependent sensory association learning. 

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4. A special role for Anterior Cingulate Cortex, but not Orbitofrontal Cortex or Basolateral Amygdala, in choices involving information

   González, V. V. (January 2023, bioRxiv)

   Humans and other animals make decisions under uncertainty. Choosing an option that provides information can improve decision making. However, subjects often choose information that does not increase the chances of obtaining reward. In a procedure that promotes such paradoxical choice, animals choose between two alternatives: The richer option is followed by a cue that is rewarded 50% of the time (No-info) and the leaner option is followed by one of two cues, one always rewarded (100%), and the other never rewarded, 0% (Info). Since decisions involve comparing the subjective value of options after integrating all their features perhaps including information value, preference for information may rely on cortico-amygdalar circuitry. To test this, male and female Long-Evans rats were prepared with bilateral inhibitory DREADDs in the anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), basolateral amygdala (BLA), or null virus infusions as a control. Using a counterbalanced design, we inhibited these regions after stable preference was acquired and during learning of new Info and No-info cues. We found that inhibition of ACC, but not OFC or BLA, selectively destabilized choice preference in female rats without affecting latency to choose or the response rate to cues. A logistic regression fit revealed that the previous choice strongly predicted preference in control animals, but not in female rats following ACC inhibition. BLA inhibition tended to decrease the learning of new cues that signaled the Info option, but had no effect on preference. The results reveal a causal, sex-dependent role for ACC in decisions involving information. 

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5. Identification of discrete, intermingled hypocretin neuronal populations

   https://doi.org/10.1002/cne.24490  

   Iyer, Manasi; Essner, Rachel A.; Klingenberg, Bernhard; Carter, Matthew E. (November 2018, Journal of Comparative Neurology)

   Abstract Neurons in the lateral hypothalamic area that express hypocretin (Hcrt) neuropeptides help regulate many behaviors including wakefulness and reward seeking. These neurons project throughout the brain, including to neural populations that regulate wakefulness, such as the locus coeruleus (LC) and tuberomammilary nucleus (TMN), as well as to populations that regulate reward, such as the nucleus accumbens (NAc) and ventral tegmental area (VTA). To address the roles of Hcrt neurons in seemingly disparate behaviors, it has been proposed that Hcrt neurons can be anatomically subdivided into at least two distinct subpopulations: a “medial group” that projects to the LC and TMN, and a “lateral group” that projects to the NAc and VTA. Here, we use a dual retrograde tracer strategy to test the hypotheses that Hcrt neurons can be classified based on their downstream projections and medial/lateral location within the hypothalamus. We found that individual Hcrt neurons were significantly more likely to project to both the LC and TMN or to both the VTA and NAc than would be predicted by chance. In contrast, we found that Hcrt neurons that projected to the LC or TMN were mostly distinct from Hcrt neurons that projected to the VTA or NAc. Interestingly, these two populations of Hcrt neurons are intermingled within the hypothalamus and cannot be classified into medial or lateral groups. These results suggest that Hcrt neurons can be distinguished based on their downstream projections but are intermingled within the hypothalamus. 

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