Research Articles: Systems/Circuits Aberrant Maturation of the Uncinate Fasciculus Follows Exposure to Unpredictable Patterns of Maternal Signals https://doi.org/10.1523/JNEUROSCI.0374-20.2020 Cite as: J. Neurosci 2020; 10.1523/JNEUROSCI.0374-20.2020 Received: 17 February 2020 Revised: 25 November 2020 Accepted: 2 December 2020 This Early Release article has been peer-reviewed and accepted, but has not been through the composition and copyediting processes. The final version may differ slightly in style or formatting and will contain links to any extended data. Alerts: Sign up at www.jneurosci.org/alerts to receive customized email alerts when the fully formatted version of this article is published. Copyright © 2020 the authors 1 Manuscript submission for Journal of Neuroscience 2 Aberrant Maturation of the Uncinate Fasciculus Follows Exposure to Unpredictable 3 Patterns of Maternal Signals 4 5 Abbreviated Title: Uncinate and Patterns of Maternal Sensory Signals 6 Steven J. Grangera,b, Laura M. Glynnc, Curt A. Sandmand, Steven L. Smalle, Andre Obenausf, 7 David B. Keatord, Tallie Z. Barama,f,g, Hal Sternh, Michael A. Yassaa,b,d ᅒ, Elysia Poggi Davisd,i 8 ᅒ 9 a Center for the Neurobiology of Learning and Memory, University of California, Irvine 92697 10 b Department of Neurobiology and Behavior, University of California, Irvine 92697 11 c Department of Psychology, Chapman University, Orange, CA 92866 12 d Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697 13 e School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX, 14 75080 15 f Department of Pediatrics, University of California, Irvine, CA 92697 16 g Department of Anatomy and Neurobiology, University of California, Irvine, CA 92697 17 h Department of Statistics, University of California, Irvine 92697 18 i Department of Psychology, University of Denver, Denver, CO 80208 19 20 ᅒCorresponding Authors 21 Michael A. Yassa Elysia Poggi Davis 22 UC Irvine University of Denver 23 [email protected] [email protected] 24 25 26 This PDF file includes: 27 43 pages 28 4 Figures, 3 tables 29 Number of words for abstract: 245 30 Number of words for introduction: 648 31 Number of words for discussion: 1,403 32 33 34 Acknowledgments: This work was supported by the National Institute of Health (Grants 35 P50MH096889 – PI: Baram; R01MH102392 – PI: Yassa; R03MH086062 – PI: Davis; NS-41298 36 – PI: Sandman, HD-51852 – PI: Sandman, and HD-28413 – PI: Sandman). 37 Conflict of Interest: The authors declare no conflicts of interest. 38 Page 1 of 29 39 Abstract 40 Across species, unpredictable patterns of maternal behavior are emerging as novel predictors of 41 aberrant cognitive and emotional outcomes later in life. In animal models, exposure to 42 unpredictable patterns of maternal behavior alters brain circuit maturation and cognitive and 43 emotional outcomes. However, whether exposure to such signals in humans alters the 44 development of brain pathways is unknown. In mother-child dyads we tested the hypothesis that 45 exposure to more unpredictable maternal signals in infancy associates with aberrant maturation 46 of corticolimbic pathways. We focused on the uncinate fasciculus, the primary fiber bundle 47 connecting the amygdala to the orbitofrontal cortex and a key component of the medial temporal 48 lobe - prefrontal cortex circuit. Infant exposure to unpredictable maternal sensory signals was 49 assessed at 6 and 12 months. Using high angular resolution diffusion imaging, we quantified the 50 integrity of the uncinate fasciculus using generalized fractional anisotropy (GFA). Higher 51 maternal unpredictability during infancy presaged greater uncinate fasciculus GFA in children 52 aged 9-11 (n=69, 29 female). In contrast to the uncinate, GFA of a second corticolimbic 53 projection, the hippocampal cingulum was not associated with maternal unpredictability. 54 Addressing the overall functional significance of the uncinate and cingulum relationships, we 55 found that the resulting imbalance of MTL-PFC connectivity partially mediated the association 56 between unpredictable maternal sensory signals and impaired episodic memory function. These 57 results suggest that unbalanced maturation of corticolimbic circuits are a mechanism by which 58 early unpredictable sensory signals may impact cognition later in life. 59 60 61 62 63 64 65 66 Page 2 of 29 67 Significance Statement 68 Our prior work across species demonstrated that unpredictable patterns of maternal care are 69 associated with compromised memory function. However, the neurobiological mechanisms by 70 which this occurs in humans remain unknown. Here, we identify an association of exposure to 71 unpredictable patterns of maternal sensory signals with the integrity of corticolimbic circuits 72 involved in emotion and cognition using state-of-the-art diffusion imaging techniques and 73 analyses. We find that exposure to early unpredictability is associated with higher integrity of the 74 uncinate fasciculus with no effect on a second corticolimbic pathway, the cingulum. The 75 resulting imbalance of corticolimbic circuit development is a novel mediator of the association 76 between unpredictable patterns of maternal care and poorer episodic memory. 77 78 79 80 81 82 83 84 85 86 87 88 89 90 Introduction Page 3 of 29 91 Experiences occurring during sensitive periods in early life are powerful factors influencing brain 92 development and cognition (Hasler et al., 2004; Andersen et al., 2008; Short & Baram, 2019). 93 Although it is clear that the quality of maternal care affects the risk for offspring psychological 94 disorders and neurobiological changes later in life (Glynn & Baram, 2019; Bowlby 1950, Lebel et 95 al., 2015), less is known about how patterns of maternal behavior impact human development 96 (Baram et al., 2012; Davis et al., 2017). Recent work has indicated that unpredictable patterns 97 of maternal sensory signals during infancy are a novel contributor to impaired cognitive and 98 emotional functions later in life (Chen & Baram, 2016, Walker et al., 2017, Glynn and Baram, 99 2019; Noraña et al., 2020; Molet et al., 2016b). 100 We previously reported in both humans and rodents that exposure to greater unpredictable 101 sensory signals during infancy is associated with memory deficits later in life (Davis et al., 2017; 102 Molet et al., 2016a; Ivy et al., 2008; Ivy et al., 2010, Bath et al., 2017). In rodents, pup exposure 103 to unpredictable maternal behavior leads to abnormal maturation of brain circuits involved with 104 memory (Brunson 2005; Guadagno et al., 2016, Walker et al., 2017; Molet et al., 2016a, Ivy et 105 al., 2010). Whether the same cortico-limbic circuits are impacted by unpredictable maternal 106 sensory signals in humans remains unknown. 107 Across species, aberrant maturation of amygdala-prefrontal circuits is well recognized as a key 108 outcome of exposure to stress (Burgos-Robles et al., 2017; Chen & Baram, 2016, Burghy et al., 109 2012, Tottenham & Galván, 2016; Gee et al., 2013). Accelerated maturation of amygdala- 110 prefrontal cortex functional connectivity may be an adaptive response to early life adversity, 111 which reprioritizes developmental goals to match the demands of adverse early life 112 environments (Gee et al., 2013). In humans, the predominant anatomical connection between 113 these two regions is the uncinate fasciculus (Ebeling and Von Cramon, 1992). The uncinate is 114 thought to be important for episodic memory and has recently been hypothesized to play an 115 important role in adjudicating among competing memory representations during retrieval (Alm et 116 al., 2016; Von der Heide et al., 2013). Abnormal development of the uncinate could lead to 117 impairments in cognitive and emotional functions (Vilgis et al., 2017; Carballedo et al., 2012; 118 Yang et al., 2017; Bhatia et al., 2018; Zhang et al., 2012). Abnormal development of the 119 uncinate has been associated with early life adversity including a history of institutionalization 120 during childhood and paternal depressive symptoms (Govindan et al., 2010; Eluvathingal et al., 121 2006, Hanson et al., 2015; Ho et al., 2017; Marroun et al., 2018). Page 4 of 29 122 Here, we evaluated whether exposure to unpredictable maternal signals in infancy is associated 123 with uncinate integrity, measured between the ages of 9 and 11. To determine whether the 124 observed effects were specific to the uncinate or are general features of corticolimbic white 125 matter, we conducted similar analyses in the hippocampal cingulum, which shares the 126 uncinate’s frontotemporal connectivity but is spatially distinct (Bubb et al., 2018). As the 127 functional output of brain circuits is a combinatorial sum of the activity of each of their 128 components (Redish and Gordon, 2017), we also conducted analyses using the ratio of 129 uncinate to hippocampal cingulum connectivity as a measure of imbalance across these two 130 pathways. 131 To determine the behavioral relevance of changes in white matter connectivity associated with 132 unpredictable maternal sensory signals, we focused on episodic memory function which we 133 assessed by using the Mnemonic Similarity Task (MST), a well-validated task (Stark, Kirwan 134 and Stark, 2019) that is sensitive to the hippocampus’ ability to discriminate among highly 135 similar experiences (i.e. pattern separation), which is thought to be a core facet of episodic 136 memory (Marr, 1971; Yassa and Stark, 2011; Leal and Yassa, 2018). This task was chosen as 137 we have previously shown across species that greater unpredictability of maternal sensory 138 signals in infancy is associated with differences in memory function (Davis et al., 2017). Further, 139 MST performance is dependent on successful adjudication among competing memory 140 representations during retrieval, which is thought to be a core function of the uncinate fasciculus 141 (Von Der Heide et al., 2013; Alm et al. 2016). 142 143 Materials and Methods 144 Participants 145 A sample of 73 mother/offspring dyads (n=30 female) from a prospective, longitudinal, prenatal 146 cohort participated.