Ben Rein, PhD is a postdoctoral scholar in the lab of Dr. Robert Malenka. In his doctoral research, Ben investigated how genetic risk factors for autism spectrum disorder alter synaptic transmission in the prefrontal cortex. Specifically, his work focused on copy number variations affecting the 16p11.2 gene locus, and identified key molecular mechanisms underlying social deficits in mouse models of 16p11.2 deletions and duplications. In his current work with Dr. Malenka, he is investigating the neural basis of empathy, and mechanisms by which empathic behavior can be enhanced.
Outside of the lab, Ben shares educational science videos on social media with the overarching goal of making science more clear and accessible to the public. He also seeks to curb misinformation on these platforms by debunking viral videos containing inaccurate claims. Through his social media channels, Ben offers guidance for students pursuing careers in science (through a video series called "Scientips") and is the Founder & President of the Aspiring Scientists Coalition, an international organization designed to provide career guidance for students in science.
Honors & Awards
LRP Award, National Institutes of Health (2022)
Postdoc JEDI Champion Award, Stanford University (2022)
Finalist, Early Career Award for Public Engagement with Science, AAAS (2022)
1st Place, Brainstorm Neuroscience Pitch Competition, Mind Science Foundation (2021)
Dean's Award for Outstanding Thesis Dissertation Research, SUNY Buffalo (2021)
Beverly P. Bishop and Charles W. Bishop Neuroscience Doctoral Thesis Award, SUNY Buffalo (2021)
Companions in Zealous Research Award, Sigma Xi (2020)
1st Place, Three Minute Thesis Competition, SUNY Buffalo (2020)
Robert F. Munn Library Scholars Award for the Outstanding Undergraduate Thesis, West Virginia University (2016)
Quin Curtis Award for the Outstanding Undergraduate Student, West Virginia University, Department of Psychology (2016)
Doctor of Philosophy, S.U.N.Y. State University at Buffalo (2021)
Bachelor of Science, West Virginia University (2016)
Robert Malenka, Postdoctoral Faculty Sponsor
Protocols for the social transfer of pain and analgesia in mice.
2022; 3 (4): 101756
We provide protocols for the social transfer of pain and analgesia in mice. We describe the steps to induce pain or analgesia (pain relief) in bystander mice with a 1-h social interaction with a partner injected with CFA (complete Freund's adjuvant) or CFA and morphine, respectively. We detail behavioral tests to assess pain or analgesia in the untreated bystander mice. This protocol has been validated in mice and rats and can be used for investigating mechanisms of empathy. For complete details on the use and execution of this protocol, please refer to Smith etal. (2021).
View details for DOI 10.1016/j.xpro.2022.101756
View details for PubMedID 36227742
Histone Deacetylase Inhibition Restores Behavioral and Synaptic Function in a Mouse Model of 16p11.2 Deletion.
The international journal of neuropsychopharmacology
BACKGROUND: Microdeletion of the human 16p11.2 gene locus confers risk for autism spectrum disorders and intellectual disability. How 16p11.2 deletion is linked to these neurodevelopmental disorders and whether there are treatment avenues for the manifested phenotypes remain to be elucidated. Emerging evidence suggests that epigenetic aberrations are strongly implicated in autism.METHODS: We performed behavioral and electrophysiological experiments to examine the therapeutic effects of epigenetic drugs in transgenic mice carrying 16p11.2 deletion (16p11del/+).RESULTS: We found that 16p11del/+ mice exhibited a significantly reduced level of histone acetylation in the prefrontal cortex (PFC). A short (3-day) treatment with class I histone deacetylase (HDAC) inhibitor MS-275 or Romidepsin led to the prolonged (3-4 weeks) rescue of social and cognitive deficits in 16p11del/+ mice. Concomitantly, MS-275 treatment reversed the hypoactivity of PFC pyramidal neurons and the hyperactivity of PFC fast-spiking (FS) interneurons. Moreover, the diminished NMDA receptor-mediated synaptic currents and the elevated GABAA receptor-mediated synaptic currents in PFC pyramidal neurons of 16p11del/+ mice were restored to control levels by MS-275 treatment.CONCLUSIONS: Our results suggest that HDAC inhibition provides a highly effective therapeutic strategy for behavioral deficits and excitation/inhibition imbalance in 16p11del/+ mice, likely via normalization of synaptic function in the PFC.
View details for DOI 10.1093/ijnp/pyac048
View details for PubMedID 35907244
A convergent mechanism of high risk factors ADNP and POGZ in neurodevelopmental disorders.
Brain : a journal of neurology
ADNP and POGZ are two top-ranking risk factors for autism spectrum disorder and intellectual disability, but how they are linked to these neurodevelopmental disorders is largely unknown. Both ADNP and POGZ are chromatin regulators, which could profoundly affect gene transcription and cellular function in the brain. Using post-mortem tissue from patients with autism spectrum disorder, we found diminished expression of ADNP and POGZ in the prefrontal cortex, a region highly implicated in neurodevelopmental disorders. To understand the functional role of these neurodevelopmental disorder risk factors, we used viral-based gene transfer to investigate how Adnp or Pogz deficiency in mouse prefrontal cortex affects behavioural, transcriptomic and synaptic function. Mice with prefrontal cortex deficiency of Adnp or Pogz exhibited specific impairment of cognitive task performance. RNA-sequencing revealed that Adnp or Pogz deficiency induced prominent upregulation of overlapping genes enriched in neuroinflammation, similar to the elevation of pro-inflammatory genes in humans with neurodevelopmental disorders. Concomitantly, Adnp or Pogz deficiency led to the significant increase of pro-phagocytic microglial activation in prefrontal cortex, as well as the significant decrease of glutamatergic transmission and postsynaptic protein expression. These findings have uncovered the convergent functions of two top risk factors for autism spectrum disorder and intellectual disability in prefrontal cortex, providing a mechanism linking chromatin, transcriptional and synaptic dysregulation to cognitive deficits associated with neurodevelopmental disorders.
View details for DOI 10.1093/brain/awac152
View details for PubMedID 35775424
Membrane Stretch Gates NMDA Receptors.
The Journal of neuroscience : the official journal of the Society for Neuroscience
N-Methyl-D-aspartic (NMDA) receptors are ionotropic glutamate receptors widely expressed in the central nervous system, where they mediate phenomena as diverse as neurotransmission, information processing, synaptogenesis, and cellular toxicity. They function as glutamate-gated Ca2+-permeable channels, which require glycine as co-agonist, and can be modulated by many diffusible ligands and cellular cues, including mechanical stimuli. Previously, we found that in cultured astrocytes, shear stress initiates NMDA receptor-mediated Ca2+ entry in the absence of added agonists, suggesting that more than being mechanosensitive, NMDA receptors may be mechanically activated. Here, we used controlled expression of rat recombinant receptors and non-invasive on-cell single-channel current recordings to show that mild membrane stretch can substitute for the neurotransmitter glutamate in gating NMDA receptor currents. Notably, stretch-activated currents maintained the hallmark features of the glutamate-gated currents, including glycine-requirement, large unitary conductance, high Ca2+ permeability, and voltage-dependent Mg2+ blockade. Further, we found that the stretch-gated current required the receptor's intracellular domain. Our results are consistent with the hypothesis that mechanical forces can gate endogenous NMDA receptor currents even in the absence of synaptic glutamate release, which has important implications for understanding mechanotransduction and the physiological and pathological effects of mechanical forces on cells of the central nervous system.Significance Statement:We show that, in addition to enhancing currents elicited with low agonist concentrations, membrane stretch can gate NMDA receptors in the absence of the neurotransmitter glutamate. Stretch-gated currents have the principal hallmarks of the glutamate-gated currents, including requirement for glycine, large Na+ conductance, high Ca2+ permeability, and voltage-dependent Mg2+ block. Therefore, results suggest that mechanical forces can initiate cellular processes presently attributed to glutamatergic neurotransmission, such as synaptic plasticity and cytotoxicity. Given the ubiquitous presence of mechanical forces in the CNS, this discovery identifies NMDA receptors as possibly important mechanotransducers during development and across the lifespan, and during pathologic processes, such as those associated with traumatic brain injuries, shaken infant syndrome, and chronic traumatic encephalopathy.
View details for DOI 10.1523/JNEUROSCI.0350-22.2022
View details for PubMedID 35705487
Targeting histone demethylase LSD1 for treatment of deficits in autism mouse models.
Large-scale genetic studies have revealed that the most prominent genes disrupted in autism are chromatin regulators mediating histone methylation/demethylation, suggesting the central role of epigenetic dysfunction in this disorder. Here, we show that histone lysine 4 dimethylation (H3K4me2), a histone mark linked to gene activation, is significantly decreased in the prefrontal cortex (PFC) of autistic human patients and mutant mice with the deficiency of top-ranking autism risk factor Shank3 or Cul3. A brief treatment of the autism models with highly potent and selective inhibitors of the H3K4me2 demethylase LSD1 (KDM1A) leads to the robust rescue of core symptoms of autism, including social deficits and repetitive behaviors. Concomitantly, LSD1 inhibition restores NMDA receptor function in PFC and AMPA receptor-mediated currentsin striatum of Shank3-deficient mice. Genome-wide RNAseq and ChIPseq reveal that treatment of Shank3-deficient mice with the LSD1 inhibitor restores the expression and H3K4me2 occupancy of downregulated genes enriched in synaptic signaling and developmental processes. The immediate early gene tightly linked to neuronal plasticity, Egr1, is on the top list of rescued genes. The diminished transcription of Egr1 is recapitulated in PFC of autistic human patients. Overexpression of Egr1 in PFC of Shank3-deficient mice ameliorates social preference deficits. These results have for the first time revealed an important role of H3K4me2 abnormality in ASD pathophysiology, and the therapeutic potential of targeting H3K4me2 demethylase LSD1 or the downstream molecule Egr1 for ASD.
View details for DOI 10.1038/s41380-022-01508-8
View details for PubMedID 35296809
Inhibition of histone deacetylase 5 ameliorates Abnormalities in 16p11.2 duplication mouse model.
Microduplication of the human 16p11.2 gene locus is associated with a range of neurodevelopmental outcomes, including autism spectrum disorder (ASD). Mice carrying heterozygous 16p11.2 duplication (16p11.2dp/+) display social deficits, which is attributable to the impaired GABAergic synaptic function in prefrontal cortex (PFC) driven by downregulation of Npas4, an activity-dependent transcription factor that regulates GABA synapse formation. However, molecular mechanisms underlying the diminished transcription of Npas4 in 16p11.2 duplication remain unknown. Npas4 is one of the target genes regulated by histone deacetylase 5 (HDAC5), an epigenetic enzyme repressing gene expression via removal of transcription-permissive acetyl groups from histones. Here we report that HDAC5 is elevated and histone acetylation is reduced in PFC of 16p11.2dp/+ mice. Treatment with the HDAC5 inhibitor LMK235 normalizes histone acetylation at Npas4 promoter, restores GABAergic signaling in PFC, and significantly improves social preference in 16p11.2dp/+ mice. These findings suggest that HDAC5 inhibition is a promising therapeutic avenue to alleviate genetic, synaptic and behavioral deficits in 16p11.2 duplication conditions.
View details for DOI 10.1016/j.neuropharm.2021.108893
View details for PubMedID 34822816
Age-related neurodegeneration and cognitive impairments of NRMT1 knockout mice are preceded by misregulation of RB and abnormal neural stem cell development.
Cell death & disease
2021; 12 (11): 1014
N-terminal methylation is an important posttranslational modification that regulates protein/DNA interactions and plays a role in many cellular processes, including DNA damage repair, mitosis, and transcriptional regulation. Our generation of a constitutive knockout mouse for the N-terminal methyltransferase NRMT1 demonstrated its loss results in severe developmental abnormalities and premature aging phenotypes. As premature aging is often accompanied by neurodegeneration, we more specifically examined how NRMT1 loss affects neural pathology and cognitive behaviors. Here we find that Nrmt1-/- mice exhibit postnatal enlargement of the lateral ventricles, age-dependent striatal and hippocampal neurodegeneration, memory impairments, and hyperactivity. These morphological and behavior abnormalities are preceded by alterations in neural stem cell (NSC) development. Early expansion and differentiation of the quiescent NSC pool in Nrmt1-/- mice is followed by its subsequent depletion and many of the resulting neurons remain in the cell cycle and ultimately undergo apoptosis. These cell cycle phenotypes are reminiscent to those seen with loss of the NRMT1 target retinoblastoma protein (RB). Accordingly, we find misregulation of RB phosphorylation and degradation in Nrmt1-/- mice, and significant de-repression of RB target genes involved in cell cycle. We also identify novel de-repression of Noxa, an RB target gene that promotes apoptosis. These data identify Nalpha-methylation as a novel regulatory modification of RB transcriptional repression during neurogenesis and indicate that NRMT1 and RB work together to promote NSC quiescence and prevent neuronal apoptosis.
View details for DOI 10.1038/s41419-021-04316-0
View details for PubMedID 34711807
Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications.
The prefrontal cortex (PFC) serves as the chief executive officer of the brain, controlling the highest level cognitive and emotional processes. Its local circuits among glutamatergic principal neurons and GABAergic interneurons, as well as its long-range connections with other brain regions, have been functionally linked to specific behaviors, ranging from working memory to reward seeking. The efficacy of synaptic signaling in the PFC network is profundedly influenced by monoaminergic inputs via the activation of dopamine, adrenergic, or serotonin receptors. Stress hormones and neuropeptides also exert complex effects on the synaptic structure and function of PFC neurons. Dysregulation of PFC synaptic transmission is strongly linked to social deficits, affective disturbance, and memory loss in brain disorders, including autism, schizophrenia, depression, and Alzheimer's disease. Critical neural circuits, biological pathways, and molecular players that go awry in these mental illnesses have been revealed by integrated electrophysiological, optogenetic, biochemical, and transcriptomic studies of PFC. Novel epigenetic mechanism-based strategies are proposed as potential avenues of therapeutic intervention for PFC-involved diseases. This review provides an overview of PFC network organization and synaptic modulation, as well as the mechanisms linking PFC dysfunction to the pathophysiology of neurodevelopmental, neuropsychiatric, and neurodegenerative diseases. Insights from the preclinical studies offer the potential for discovering new medical treatments for human patients with these brain disorders.
View details for DOI 10.1038/s41380-021-01092-3
View details for PubMedID 33875802
Synergistic inhibition of histone modifiers produces therapeutic effects in adult Shank3-deficient mice
2021; 11 (1): 99
Autism spectrum disorder (ASD) is a lifelong developmental disorder characterized by social deficits and other behavioral abnormalities. Dysregulation of epigenetic processes, such as histone modifications and chromatin remodeling, have been implicated in ASD pathology, and provides a promising therapeutic target for ASD. Haploinsufficiency of the SHANK3 gene is causally linked to ASD, so adult (3-5 months old) Shank3-deficient male mice were used in this drug discovery study. We found that combined administration of the class I histone deacetylase inhibitor Romidepsin and the histone demethylase LSD1 inhibitor GSK-LSD1 persistently ameliorated the autism-like social preference deficits, while each individual drug alone was largely ineffective. Another behavioral abnormality in adult Shank3-deficient male mice, heightened aggression, was also alleviated by administration of the dual drugs. Furthermore, Romidepsin/GSK-LSD1 treatment significantly increased transcriptional levels of NMDA receptor subunits in prefrontal cortex (PFC) of adult Shank3-deficient mice, resulting in elevated synaptic expression of NMDA receptors and the restoration of NMDAR synaptic function in PFC pyramidal neurons. These results have offered a novel pharmacological intervention strategy for ASD beyond early developmental periods.
View details for DOI 10.1038/s41398-021-01233-w
View details for Web of Science ID 000617327100006
View details for PubMedID 33542189
View details for PubMedCentralID PMC7862604
16P11.2 Copy Number Variations and Neurodevelopmental Disorders
TRENDS IN NEUROSCIENCES
2020; 43 (11): 886–901
Copy number variations (CNVs) of the human 16p11.2 genetic locus are associated with a range of neurodevelopmental disorders, including autism spectrum disorder, intellectual disability, and epilepsy. In this review, we delineate genetic information and diverse phenotypes in individuals with 16p11.2 CNVs, and synthesize preclinical findings from transgenic mouse models of 16p11.2 CNVs. Mice with 16p11.2 deletions or duplications recapitulate many core behavioral phenotypes, including social and cognitive deficits, and exhibit altered synaptic function across various brain areas. Mechanisms of transcriptional dysregulation and cortical maldevelopment are reviewed, along with potential therapeutic intervention strategies.
View details for DOI 10.1016/j.tins.2020.09.001
View details for Web of Science ID 000582637600006
View details for PubMedID 32993859
View details for PubMedCentralID PMC7606557
A standardized social preference protocol for measuring social deficits in mouse models of autism
2020; 15 (10): 3464–77
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social communication deficits and other behavioral abnormalities. The three-chamber social preference test is often used to assess social deficits in mouse models of ASD. However, varying and often contradicting phenotypic descriptions of ASD mouse models can be found in the scientific literature, and the substantial variability in the methods used by researchers to assess social deficits in mice could be a contributing factor. Here we describe a standardized three-chamber social preference protocol, which is sensitive and reliable at detecting social preference deficits in several mouse models of ASD. This protocol comprises three phases that can all be completed within 1 d. The test mouse is first habituated to the apparatus containing two empty cups in the side chambers, followed by the pre-test phase in which the mouse can interact with two identical inanimate objects placed in the cups. During the test phase, the mouse is allowed to interact with a social stimulus (an unfamiliar wild-type (WT) mouse) contained in one cup and a novel non-social stimulus contained in the other cup. The protocol is thus designed to assess preference between social and non-social stimuli under conditions of equal salience. The broad implementation of the three-chamber social preference protocol presented here should improve the accuracy and consistency of assessments for social preference deficits associated with ASD and other psychiatric disorders.
View details for DOI 10.1038/s41596-020-0382-9
View details for Web of Science ID 000566859200001
View details for PubMedID 32895524
Reversal of synaptic and behavioral deficits in a 16p11.2 duplication mouse model via restoration of the GABA synapse regulator Npas4
The human 16p11.2 gene locus is a hot spot for copy number variations, which predispose carriers to a range of neuropsychiatric phenotypes. Microduplications of 16p11.2 are associated with autism spectrum disorder (ASD), intellectual disability (ID), and schizophrenia (SZ). Despite the debilitating nature of 16p11.2 duplications, the underlying molecular mechanisms remain poorly understood. Here we performed a comprehensive behavioral characterization of 16p11.2 duplication mice (16p11.2dp/+) and identified social and cognitive deficits reminiscent of ASD and ID phenotypes. 16p11.2dp/+ mice did not exhibit the SZ-related sensorimotor gating deficits, psychostimulant-induced hypersensitivity, or motor impairment. Electrophysiological recordings of 16p11.2dp/+ mice found deficient GABAergic synaptic transmission and elevated neuronal excitability in the prefrontal cortex (PFC), a brain region critical for social and cognitive functions. RNA-sequencing identified genome-wide transcriptional aberrance in the PFC of 16p11.2dp/+ mice, including downregulation of the GABA synapse regulator Npas4. Restoring Npas4 expression in PFC of 16p11.2dp/+ mice ameliorated the social and cognitive deficits and reversed GABAergic synaptic impairment and neuronal hyperexcitability. These findings suggest that prefrontal cortical GABAergic synaptic circuitry and Npas4 are strongly implicated in 16p11.2 duplication pathology, and may represent potential targets for therapeutic intervention in ASD.
View details for DOI 10.1038/s41380-020-0693-9
View details for Web of Science ID 000516342900002
View details for PubMedID 32099100
View details for PubMedCentralID PMC7483162
Diminished social interaction incentive contributes to social deficits in mouse models of autism spectrum disorder
GENES BRAIN AND BEHAVIOR
2020; 19 (1): e12610
One of the core symptoms of autism spectrum disorder (ASD) is impaired social interaction. Currently, no pharmacotherapies exist for this symptom due to complex biological underpinnings and distinct genetic models which fail to represent the broad disease spectrum. One convincing hypothesis explaining social deficits in human ASD patients is amotivation, however it is unknown whether mouse models of ASD represent this condition. Here we used two highly trusted ASD mouse models (male Shank3-deficient [Shank3+/ΔC ] mice modeling the monogenic etiology of ASD, and inbred BTBR mice [both male and female] modeling the idiopathic and highly polygenic pathology for ASD) to evaluate the level of motivation to engage in a social interaction. In the behavioral paradigms utilized, a social stimulus was placed in the open arm of the elevated plus maze (EPM), or the light compartment of the light-dark box (LDB). To engage in a social interaction, mice were thus required to endure innately aversive conditions (open areas, height, and/or light). In the modified EPM paradigm, both Shank3+/ΔC and BTBR mice demonstrated decreased open-arm engagement with a social stimulus but not a novel object, suggesting reduced incentive to engage in a social interaction in these models. However, these deficits were not expressed under the less severe aversive pressures of the LDB. Collectively, we show that ASD mouse models exhibit diminished social interaction incentive, and provide a new investigation strategy facilitating the study of the neurobiological mechanisms underlying social reward and motivation deficits in neuropsychiatric disorders.
View details for DOI 10.1111/gbb.12610
View details for Web of Science ID 000494581700001
View details for PubMedID 31602784
Chemogenetic Activation of Prefrontal Cortex Rescues Synaptic and Behavioral Deficits in a Mouse Model of 16p11.2 Deletion Syndrome
JOURNAL OF NEUROSCIENCE
2018; 38 (26): 5939–48
Microdeletion of the human 16p11.2 gene locus has been linked to autism spectrum disorder (ASD) and intellectual disability and confers risk for a number of other neurodevelopmental deficits. Transgenic mice carrying 16p11.2 deletion (16p11+/-) display phenotypes reminiscent of those in human patients with 16p11.2 deletion syndrome, but the molecular mechanisms and treatment strategies for these phenotypes remain unknown. In this study, we have found that both male and female 16p11+/- mice exhibit deficient NMDA receptor (NMDAR) function in the medial prefrontal cortex (mPFC), a brain region critical for high-level "executive" functions. Elevating the activity of mPFC pyramidal neurons with a CaMKII-driven Gq-DREADD (Gq-coupled designer receptors exclusively activated by designer drugs) led to the significant increase of NR2B subunit phosphorylation and the restoration of NMDAR function, as well as the amelioration of cognitive and social impairments in 16p11+/- mice. These results suggest that NMDAR hypofunction in PFC may contribute to the pathophysiology of 16p11.2 deletion syndrome and that restoring PFC activity is sufficient to rescue the behavioral deficits.SIGNIFICANCE STATEMENT The 16p11.2 deletion syndrome is strongly associated with autism spectrum disorder and intellectual disability. Using a mouse model carrying the 16p11.2 deletion, 16p11+/-, we identified NMDA receptor hypofunction in the prefrontal cortex (PFC). Elevating the activity of PFC pyramidal neurons with a chemogenetic tool, Gq-DREADD, led to the restoration of NMDA receptor function and the amelioration of cognitive and social impairments in 16p11+/- mice. These results have revealed a novel route for potential therapeutic intervention of 16p11.2 deletion syndrome.
View details for DOI 10.1523/JNEUROSCI.0149-18.2018
View details for Web of Science ID 000438372400011
View details for PubMedID 29853627
View details for PubMedCentralID PMC6021990
Evaluation of an avatar-based training program to promote suicide prevention awareness in a college setting
JOURNAL OF AMERICAN COLLEGE HEALTH
2018; 66 (5): 401–11
Training programs exist that prepare college students, faculty, and staff to identify and support students potentially at risk for suicide. Kognito is an online program that trains users through simulated interactions with virtual humans. This study evaluated Kognito's effectiveness in preparing users to intervene with at-risk students.Training was completed by 2,727 university students, faculty, and staff from April, 2014 through September, 2015.Voluntary and mandatory participants at a land-grant university completed Kognito modules designed for higher education, along with pre- and post-assessments.All modules produced significant gains in reported Preparedness, Likelihood, and Self-Efficacy in intervening with troubled students. Despite initial disparities in reported abilities, after training participants reported being similarly capable of assisting at-risk students, including LGBTQ and veteran students.Kognito training appears to be effective, on a large scale, in educating users to act in a facilitative role for at-risk college students.
View details for DOI 10.1080/07448481.2018.1432626
View details for Web of Science ID 000435334700008
View details for PubMedID 29461940