Eisch Lab Academic Accomplishment Highlights

Identified a novel hippocampal circuit to combat negative valence systems and stress-induced social avoidance.

Major depressive disorder (MDD) is considered a ‘circuitopathy’, and brain stimulation therapies hold promise for ameliorating MDD symptoms, including hippocampal and dentate gyrus dysfunction. It is unknown whether stimulation of "upstream" dentate gyrus circuitry, such as the entorhinal cortex (Ent), is antidepressive, although Ent stimulation improves learning and memory in mice and humans. To this end, the Eisch Lab showed that molecular targeting (Ent-specific knockdown of a psychosocial stress-induced protein) and chemo-genetic stimulation of Ent neurons induce antidepressive-like effects in mice. Mechanistically, we show that Ent-stimulation-induced antidepressive-like behavior relies on the generation of new hippocampal neurons. Thus, controlled stimulation of Ent hippocampal afferents is antidepressive via increased hippocampal neurogenesis. These findings emphasize the power and potential of Ent glutamatergic afferent stimulation—previously well-known for its ability to influence learning and memory— for MDD treatment. Beginning in 2023, we have a grant from the National Institutes of Health/National Institute on Mental Health (NIH/NIMH) to define how this pathways contributes to a fundamental cognitive process: the ability to distinguish between highly-similar events. 

Pioneered the bidirectional relationship between drugs of abuse and the birth and differentiation of new neurons in the adult rodent dentate gyrus. For example, we have shown:

a.   Cocaine self-administration in rats decreases hippocampal neurogenesis in the short-term, but longer-term administration (or cessation) increases aberrant hippocampal neurogenesis. This study builds off work Dr. Eisch did as a postdoc in the Nestler Lab where she showed that experimenter-delivered morphine and self-administered heroin both negatively influence aspects of postnatal dentate gyrus neurogenesis. However Dr. Eisch's more recent study with cocaine from her own lab highlights a novel aspect of neuroplasticity that occurs after a drug of abuse, and underscore that even short-term administration sets in motion sequelae that may contribute to cocaine-induced cognitive dysfunction. 

b.   Ablation of adult hippocampal neurogenesis (via cranial image-guided irradiation) leads to greater vulnerability in a rat model of cocaine addiction as well as in a rat model of morphine addiction. By showing new neurons in the adult brain regulate a reward-based behavior, these papers open a completely new avenue for studying how hippocampal circuitry contributes to reward-based behavior.

c. A novel role for adult neurogenesis in reward-based memories and particularly the extinction rate of these memories. If an animal receives a typically rewarding drug, like morphine, in a novel environment, it may form a positive association with that environment and want to return to that context later when given a choice. This "drug-context" association is a key step in the process of addiction, and the role of new neurons in the formation and persistence of drug-context associations were unknown. Here we used image-guided, hippocampal-targeted X-ray irradiation to decrease mouse neurogenesis, and tested mice in conditioned place preference (CPP, a behavioral test of how well they form memories of a novel context in which they receive morphine) at recent (<48 hr post-CPP training) and remote (>1 week post-CPP training) timepoints. Image-guided irradiation did  mice change the formation or retrieval of recent or remote morphine-context memories. However, relative to control mice irradiated mice had increased persistence of recent - but not remote - morphine-associated reward memory; the extinction of the drug-context memory took longer. Consideration of this work may lead to better understanding of extinction-based behavioral interventions for psychiatric conditions characterized by dysregulated reward processing.

d. Importantly, we have also shown that exposure to drugs of abuse does not always have negative effects on neurogenesis. Recently we have shown that indices of dentate gyrus neurogenesis are unaffected immediately after or following withdrawal from morphine self-administration compared to saline self-administering control male rats. These negative data highlight the impact experimental parameters, time point selection, and quantification approach have on neurogenesis results, and we believe are important in the context of the large literature showing the negative impact of opiates on DG neurogenesis. While our future plans are still evolving, it may be interesting to see if and how dentate gyrus neurogenesis is influenced in models of opioid rat self-administration - such as rat oral oxycodone self-administration with which we have recently published. 

Identified a novel role for postnatal-generated dentate gyrus neurons in the adult rodent brain in stress-induced social avoidance.

Using an ethologically-relevant model of social stress, we showed that – in contrast to a long held belief that “stress decreases neurogenesis” – mice susceptible to social defeat stress show enhanced hippocampal neurogenesis, and that ablation of new neurons makes susceptible mice “resilient” to stress-induced social avoidance. These results fit perfectly with the general (and still widely accepted) concept that “new neurons = better memory”, but were paradigm-shifting in that they showed that “stress can increase neurogenesis”, and that this increase can be interpreted as a survival strategy. Given our recent collaborative work with Dr. Ann Stowe showing that key immune cells migrate into remote brain areas and support neurogenesis and functional recovery in a mouse model of brain injury, ongoing work is evaluating the evolving role of the immune system in stress-induced responses and altered neurogenesis. 

Defined a palette of genes that contribute to the molecular, cell-autonomous regulation of postnatal dentate gyrus neurogenesis. 

This paper was the first of many Eisch Lab papers that used the novel mouse model that we generated (nestin-CreERT2 mouse) to selectively delete discrete genes from neural stem cells and their progeny in vivo. In further publications we worked alone and with collaborators to identify stages of postnatal new neuron development that rely on a variety of genes: Cdk5, Notch1, NeuroD, FMRP, Brg1, and Reelin. These findings are important for many reasons, including that they reveal “druggable” targets to regulate neurogenesis (e.g. Cdk5), and that they emphasize the responsiveness of the neurogenic niche to changes in neurogenesis (e.g. Notch1). Taken together, these are among the first studies to inducibly delete a gene from the entire population of nestin-expressing stem cells and their progeny in vivo, and also among the first to assess both neurogenesis and behavior in the resulting mutant mice. We were also pleased to have deposited this transgenic mouse line at Jackson Laboratories, as 100+ laboratories acquired the nestin-CreERT2 mouse from the Eisch laboratory directly, and now even more labs can acquire it directly from Jackson Labs (C57BL/6-Tg(Nes-cre/ERT2)KEisc/J, Stock No: 016261).

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Discovered in vivo functional evidence for heterogeneity of neural stem cells in the adult mouse hippocampus. 

Prior work suggested that there was a single, linear path from stem cells to adult-generated neurons in the hippocampus, and that this path went from GLAST- or GFAP-expressing radial glial cells (RGCs) through nestin-expressing neural stem cells to their neural progenitor progeny. However, our comparison of the contribution of neurogenesis from nestin-expressing vs. glast-expressing stem cells basally, after injury, and after running revealed a striking heterogeneity of these two putative stem cell population: GLAST-expressing radial glia cells contribute to long-term hippocampal neurogenesis, while nestin-expressing radial glia cells do not. These findings are important for the field, as they raise important questions about the differences between transgenic driver lines used in the literature; the heterogeneity of radial glial cells; and the potential differences in progenitor cell behavior between transgenic lines. As these findings highlight the possible differences in the contribution of cells to long-term neurogenesis in vivo, they indicate that the current models of hippocampal neurogenesis should be modified to include RGC lineage heterogeneity.

Provided cutting-edge understanding of the effects of galactic cosmic radiation and space flight on the rodent central nervous system. 

Neural stem cells have in the past been considered highly sensitive to the influence of both X-ray and space radiation, with their numbers reportedly unchanged after radiation (according to reporter mouse studies). However, using our nestin-CreERT2 inducible transgenic mice, we were able to show that in fact stem cell number does not change over time, but rather stem cell function (and therefore their number of progeny) decreases. We also made three findings with great importance to NASA. First, we discovered that in regards to adult neurogenesis, fractionated exposure to space radiation is no more detrimental than a single exposure of space radiation. This means that NASA’s ground-based space radiation work (which typically uses a single exposure) has relevance for the longer, fractionated exposure that astronauts will receive in space. Second, we discovered that olfactory neurogenesis in mice that flew on the last space shuttle mission is compromised relative to grounded control mice, a finding which may help explain olfactory deficits that occur after lengthy space missions. Finally, we recently made the striking discovery of an age-dependent effect of space radiation on rodent brain function: young mice have diminished hippocampal function after space radiation exposure, but older mice (the equivalent age of astronauts) have improved hippocampal function. We are currently exploring the neural mechanisms underlying this age-dependent effect, but NASA is particularly interested in this latter work since all prior work with space radiation has been done with young rodents (the equivalent age of teenagers). In 2024, Eisch Lab members Drs. Colón, Eisch, Kiffer, and Yun were co-authors on an international collaboration published in Nature Communications titled,"Cosmic kidney disease: an integrated pan-omic, physiological and morphological study into spaceflight-induced renal dysfunction". This huge project used samples from rodents and human astronauts to show that exposure to a Mars roundtrip dose-equivalent of simulated galactic cosmic radiation (GCR) lead to renal damage and dysfunction.

Videos/Podcasts of Dr. Eisch:

Eisch AJ. Video of presentation as Inaugural Seymour Benzer Lecturer, National Academy of Sciences. Sponsored by Nobel Laureate Sydney Brenner to honor researcher in neuroscience or genetics. Presented as part of “Distinctive Voices @ The Beckman Center” for the Kavli Frontiers of Science and the National Academy of Sciences, Irvine, CA (2011)

Eisch AJ. Video of keynote lecture for the 25th annual NEURON (NorthEast Undergraduate Research Organization for Neuroscience) Conference. Held at Quinnipiac University (2014)

Eisch AJ. Interviewed for Brain Matters, UT Austin Graduate Student Podcast or available via iTunes in Brain Matters podcast, episode released July 1, 2015. Recorded in Austin, TX (2014)

Eisch AJ. “A Stimulating Question: Can a Neural Circuit of Memory Be Harnessed To Drive Anti-Depressive Like Behavior?” Speaker for virtual 15th Penn Neuroscience Public Lecture Series. Crowdcast link (2022)