Developmental underpinnings of differences in rodent novelty‐seeking and emotional reactivity

“The hippocampus plays a well-known and long-established role in learning and memory functions (Eichenbaum et al., 1992; Squire, 1992).”

“Cell intensity files from the AffymetrixGeneChip arrays were normalized by the robust multiarray average (RMA) algorithm (Irizarry et al., 2003).”

“Thus, excessive anxiety may derive from over-activation of this behavioral inhibition circuit (Gray, 1982), leading to exaggerated threat perception in situations where that response is unwarranted.”

“…stress reactivity and anxiety compared to offspring of low licking, grooming and arched-back nursing mothers, and that these effects were driven in part through changes in the hippocampus (Liu et al., 1997; Stern, 1997; Caldji et al., 1998; Meaney, 2001; Weaver et al., 2002; Bredy et al., 2003).”

“Using Stereo Investigator software (MicroBrightField, Williston, VT, USA) and a computer-interfaced microscope and, following the rules of design-based stereology (West et al., 1991), we systematically sampled through the hippocampus.”

“The left and right hippocampi were identified on an average of 21 sections (range 18–22 sections), and hippocampal volume was estimated using the Cavalieri principle (Gundersen et al., 1988).”

“Their work showed how highly maternal rat mothers raise offspring with diminished stress reactivity and anxiety compared to offspring of low licking, grooming and arched-back nursing mothers, and that these effects were driven in part through changes in the hippocampus (Liu et al., 1997; Stern, 1997; Caldji et al., 19…”

“…the hippocampus detects novelty (Roullet & Lassalle, 1990; Lever et al., 2006; Jeewajee et al., 2008), regulates neural stress circuits (Sapolsky et al., 1984; Jacobson & Sapolsky, 1991) and controls fear and anxiety-like behavior (Gray, 1982; McNaughton & Gray, 2000; Bannerman et al., 2002).”

“Some clinical work using twin studies and post-traumatic stress disorder (PTSD) suggests that hippocampal size in the nonexposed twin can predict the magnitude of PTSD in the twin who undergoes combat trauma (Bremner et al., 1995; Mueser et al., 2002).”

“purchased LR and HR rats (Piazza et al., 1989) exhibiting differences in psychostimulant reactivity and self-administration.”

“The hippocampus plays a well-known and long-established role in learning and memory functions (Eichenbaum et al., 1992; Squire, 1992).”

“We examined cell proliferation in the dentate gyrus of developing bHR and bLR animals via immunohistochemical labeling of Ki-67, an endogenous marker of ongoing cell proliferation (Kee et al., 2002).”

“…1999), demonstrating that toddlers with high levels of behavioral inhibition (acting fearful in novel situations) show increased risk for developing anxiety disorders and depression (Caspi et al., 1996; Hayward et al., 1998; Schwartz et al., 1999; Biederman et al., 2001; Muris et al., 2001).”

“, 2008), regulates neural stress circuits (Sapolsky et al., 1984; Jacobson & Sapolsky, 1991) and controls fear and anxiety-like behavior (Gray, 1982; McNaughton & Gray, 2000; Bannerman et al.”

“…raw Ct values based on normalized input amounts of cDNA has recently been validated and is advantageous because it does not rely on normalization to housekeeping genes whose expression may differ among experimental groups, especially during development (Dheda et al., 2005; Libus & Storchova, 2006).”

“…1999), demonstrating that toddlers with high levels of behavioral inhibition (acting fearful in novel situations) show increased risk for developing anxiety disorders and depression (Caspi et al., 1996; Hayward et al., 1998; Schwartz et al., 1999; Biederman et al., 2001; Muris et al., 2001).”

“, 2005), which may be relevant to the bHR–bLR model considering their known differences in addictive behavior (Flagel et al., 2009).”

“…the hippocampus detects novelty (Roullet & Lassalle, 1990; Lever et al., 2006; Jeewajee et al., 2008), regulates neural stress circuits (Sapolsky et al., 1984; Jacobson & Sapolsky, 1991) and controls fear and anxiety-like behavior (Gray, 1982; McNaughton & Gray, 2000; Bannerman et al., 2002).”

“Some clinical work using twin studies and post-traumatic stress disorder (PTSD) suggests that hippocampal size in the nonexposed twin can predict the magnitude of PTSD in the twin who undergoes combat trauma (Bremner et al., 1995; Mueser et al., 2002).”

“We confirmed select microarray findings via qRT-PCR using a BioRadiCycler (Bio-Rad, Hercules, CA, USA) with SYBR green detection chemistry (Bustin, 2004) as previously described (Bernard et al., 2010).”

“For example, the hippocampus detects novelty (Roullet & Lassalle, 1990; Lever et al., 2006; Jeewajee et al., 2008), regulates neural stress circuits (Sapolsky et al., 1984; Jacobson & Sapolsky, 1991) and controls fear and anxiety-like behavior (Gray, 1982; McNaughton & Gray, 2000; Bannerman et al.,…”

“These distinct behavioral characteristics are reminiscent of the child temperament differences described by Kagan & Snidman (1999); thus, the bLR–bHR model may be useful for studying the underlying developmental neurobiology of temperament.”

“, 1984; Jacobson & Sapolsky, 1991) and controls fear and anxiety-like behavior (Gray, 1982; McNaughton & Gray, 2000; Bannerman et al., 2002).”

“Interestingly, many previously reported gene expression differences in non-selectively-bred LR/HR rats involve the hippocampus (Rosario & Abercrombie, 1999; Kabbaj et al., 2000; Kabbaj, 2004; Kabbaj et al., 2004; Ballaz et al., 2007).”

“…for high novelty exploration (bred High Responder; bHR) also exhibit exaggerated aggression, impulsivity and proclivity to psychostimulant abuse (Flagel et al., 2010) compared to bred Low Responder (bLR) rats, which exhibit enhanced anxiety, depression and vulnerability to chronic stress (Stead…”

“Several studies point to differences within dopaminergic circuits, particularly accumbal dopamine transmission, that may underlie these effects (Hooks et al., 1991, 1994; Hooks & Kalivas, 1995; Flagel et al., 2010).”

“…similar results across several published studies that were conducted by different investigators using the bHR and bLR rats (e.g. anxiety behavior: Stead et al., 2006a; Clinton et al., 2008; Perez et al., 2009; Stedenfeld et al., 2011; Turner et al., 2011; or addictive behavior: Davis et al.,…”

“Their work showed how highly maternal rat mothers raise offspring with diminished stress reactivity and anxiety compared to offspring of low licking, grooming and arched-back nursing mothers, and that these effects were driven in part through changes in the hippocampus (Liu et al., 1997; Stern, 1997; Caldji et al., 19…”

“…Grm3) suppresses exaggerated glutamatergic synaptic activity, reduces anxiety and stress responsivity in rodents, and alleviates anxiety in humans (Schoepp et al., 2003). bHRs’ increased expression may contribute, at least in part, to their low levels of anxiety compared to bLR. Future efforts…”

“For example, the hippocampus detects novelty (Roullet & Lassalle, 1990; Lever et al., 2006; Jeewajee et al., 2008), regulates neural stress circuits (Sapolsky et al., 1984; Jacobson & Sapolsky, 1991) and controls fear and anxiety-like behavior (Gray, 1982; McNaughton & Gray, 2000; Bannerman et al.,…”

“bHR rats (evident, for example, in enhanced hippocampal volume) may contribute to an exaggerated degree of behavioral inhibition (McNaughton, 1997; Lemaire et al., 1999).”

“Abundant evidence demonstrates how gene · environment interactions can alter developing brain circuits and impact risk for emotional disorder (Leonardo & Hen, 2008).”

“Several studies point to differences within dopaminergic circuits, particularly accumbal dopamine transmission, that may underlie these effects (Hooks et al., 1991, 1994; Hooks & Kalivas, 1995; Flagel et al., 2010).”

“Several studies point to differences within dopaminergic circuits, particularly accumbal dopamine transmission, that may underlie these effects (Hooks et al., 1991; Hooks et al., 1994; Hooks & Kalivas, 1995; Flagel et al., 2010).”

“In that model, the HAB and LAB females’ behavioral differences (in both maternal behavior and anxiety) were contingent upon oxytocin and vasopressin levels in select brain areas (Bosch, 2011).”

“…by different investigators using the bHR and bLR rats (e.g. anxiety behavior: Stead et al., 2006a; Clinton et al., 2008; Perez et al., 2009; Stedenfeld et al., 2011; Turner et al., 2011; or addictive behavior: Davis et al., 2008; Flagel et al., 2010; Cummings et al., 2011; Flagel et al., 2011).”

“bHR rats (evident, for example, in enhanced hippocampal volume) may contribute to an exaggerated degree of behavioral inhibition (McNaughton, 1997; Lemaire et al., 1999).”

“conducted by different investigators using the bHR and bLR rats (e.g. anxiety behavior: Stead et al., 2006a; Clinton et al., 2008; Perez et al., 2009; Stedenfeld et al., 2011; Turner et al., 2011; or addictive behavior: Davis et al., 2008; Flagel et al., 2010; Cummings et al., 2011; Flagel et al., 2011).”

“…1999), demonstrating that toddlers with high levels of behavioral inhibition (acting fearful in novel situations) show increased risk for developing anxiety disorders and depression (Caspi et al., 1996; Hayward et al., 1998; Schwartz et al., 1999; Biederman et al., 2001; Muris et al., 2001).”

“, 2006), as well as a human study that found a positive correlation between trait anxiety and hippocampal volume (Rusch et al., 2001).”

“…similar results across several published studies that were conducted by different investigators using the bHR and bLR rats (e.g. anxiety behavior: Stead et al., 2006a; Clinton et al., 2008; Perez et al., 2009; Stedenfeld et al., 2011; Turner et al., 2011; or addictive behavior: Davis et al.,…”

“low anxiety (Kalisch et al., 2006), as well as a human study that found a positive correlation between trait anxiety and hippocampal volume (Rusch et al.”

“These maturational processes involve several stages, including synaptogenesis (thought to occur within the first two postnatal weeks), synaptic pruning and shifts in synaptic targeting, as well as alterations of the precise composition of preand post-synaptic molecules (Dumas, 2005).”

“…by different investigators using the bHR and bLR rats (e.g. anxiety behavior: Stead et al., 2006a; Clinton et al., 2008; Perez et al., 2009; Stedenfeld et al., 2011; Turner et al., 2011; or addictive behavior: Davis et al., 2008; Flagel et al., 2010; Cummings et al., 2011; Flagel et al., 2011).”

“…by different investigators using the bHR and bLR rats (e.g. anxiety behavior: Stead et al., 2006a; Clinton et al., 2008; Perez et al., 2009; Stedenfeld et al., 2011; Turner et al., 2011; or addictive behavior: Davis et al., 2008; Flagel et al., 2010; Cummings et al., 2011; Flagel et al., 2011).”

“For example, the hippocampus detects novelty (Roullet & Lassalle, 1990; Lever et al., 2006; Jeewajee et al., 2008), regulates neural stress circuits (Sapolsky et al., 1984; Jacobson & Sapolsky, 1991) and controls fear and anxiety-like behavior (Gray, 1982; McNaughton & Gray, 2000; Bannerman et al.,…”

“The rodent hippocampus undergoes an amazing degree of growth and development during the early postnatal weeks, analogous to a similar growth spurt occurring during the first postnatal year in human and primate hippocampus (Insausti et al., 2010).”

“Their work showed how highly maternal rat mothers raise offspring with diminished stress reactivity and anxiety compared to offspring of low licking, grooming and arched-back nursing mothers, and that these effects were driven in part through changes in the hippocampus (Liu et al., 1997; Stern, 1997; Caldji et al., 19…”

“Interestingly, many previously reported gene expression differences in non-selectively-bred LR and HR rats involve the hippocampus (Rosario & Abercrombie, 1999; Kabbaj et al., 2000, 2004; Kabbaj, 2004; Ballaz et al., 2007).”

“Interestingly, many previously reported gene expression differences in non-selectively-bred LR and HR rats involve the hippocampus (Rosario & Abercrombie, 1999; Kabbaj et al., 2000, 2004; Kabbaj, 2004; Ballaz et al., 2007).”

“Interestingly, many previously reported gene expression differences in non-selectively-bred LR and HR rats involve the hippocampus (Rosario & Abercrombie, 1999; Kabbaj et al., 2000, 2004; Kabbaj, 2004; Ballaz et al., 2007).”

“…several published studies that were conducted by different investigators using the bHR and bLR rats (e.g. anxiety behavior: Stead et al., 2006a; Clinton et al., 2008; Perez et al., 2009; Stedenfeld et al., 2011; Turner et al., 2011; or addictive behavior: Davis et al., 2008; Flagel et al.,…”

“Interestingly, many previously reported gene expression differences in non-selectively-bred LR/HR rats involve the hippocampus (Rosario & Abercrombie, 1999; Kabbaj et al., 2000; Kabbaj, 2004; Kabbaj et al., 2004; Ballaz et al., 2007).”

“Our disparate findings may be related to a host of factors that include the developmental window of increased maternal behavior, and genetic factors inherent to the rat strain (Clinton et al., 2007).”

“, 2004), a difference linked to emotionality and anxiety (Belzung, 1992; Prior et al., 1997).”

“, 2004), a difference linked to emotionality and anxiety (Belzung, 1992; Prior et al., 1997).”

“…raw Ct values based on normalized input amounts of cDNA has recently been validated and is advantageous because it does not rely on normalization to housekeeping genes whose expression may differ among experimental groups, especially during development (Dheda et al., 2005; Libus & Storchova, 2006).”

“Tissue was Cresyl violet-stained and boundaries of the hippocampus were defined consistently across subjects based on morphologic appearance and cytoarchitectural landmarks (West et al., 1991; Fitting et al., 2008).”

“Following this burst of synaptogenesis, several additional days and even weeks are required for synaptic connections and hippocampal circuits to fully mature (Waters et al., 1997).”

“We chose a paradigm that evaluates spatial exploration in infant rats (Loewen et al., 2005).”

“Although bHR dams exhibited less maternal behavior than bLRs during the dark/active phase, they were very attentive to their pups during the light phase, spending greater time in passive nursing and in contact with pups compared to bLR dams (Clinton et al., 2007; Clinton et al., 2010).”

“pal structural differences that may contribute to their behavior (Lemaire et al., 1999; Isgor et al., 2004).”

“Data had been generated using Affymetrix Mouse Genome 430 2.0 or Rat Genome U34 microarrays, and acquired from the Gene Expression Omnibus (dataset series GSE29552) [29] or the author [28].”

“In fact, in experiments not focused on drug behavior, HR rats are less prone to depression-like behavior compared to LR controls (Clinton et al., 2011; Stedenfeld et al., 2011).”

“As found in RHA and RLA rats, these two rat sub-lines also exhibit several different behavioral traits: bNEHR rats show exaggerated aggression [264], impulsivity and proclivity to addictive behaviors [265–267] when compared with bNELR rats, which exhibit exaggerated anxiety and immobility [268,269], depressive-like be…”

“…compared to bHRs, adult bLR rats exhibit lower Tph2, Sert (Kerman et al., 2011) and 5ht1a receptor (Calvo et al., 2011) mRNA in the dorsal raphe, and increased 5ht1a (Clinton et al., 2011a), 5ht2a (Calvo et al., 2011), 5ht6 and 5ht7 (Ballaz et al., 2007b) receptor mRNA in multiple limbic regions.”

“…(Cummings et al., 2011; Davis et al., 2008; Flagel et al., 2010) compared to low novelty reactive rats (bred Low Responders, bLRs), which show high levels of anxiety- and depressive-like behavior (Clinton et al., 2008, 2011b; Perez et al., 2009; Stead et al., 2006; Stedenfeld et al., 2011).”

“Our results revealed dramatic gene expression differences in the developing hippocampus of bHR versus bLR during the first two weeks of life [11].”

“Based on the dramatic HR/LR transcriptome differences in the early postnatal amygdala and hippocampus [35,44], we sought”

“Our prior work with the bred HR and LR lines shows that the HR/LR behavioral traits emerge during the first weeks of life (Clinton et al., 2008, 2011), and that the traits are associated with distinct patterns of hippocampal development (Clinton et al., 2011; Turner et al., 2011).”

“, 2015), and these differences are observable as early as the 25th day of life (Clinton et al., 2011).”

“We performed qRT-PCR as described [18] on a StepOne Plus (Applied Biosystems, Grand Island, NY, USA).”

“This is not particularly surprising since the hippocampus plays a fundamental role in regulating motivated behavior (Ito et al. 2005) and has been associated with differences in temperament (Oler et al. 2010) and environmental reactivity to stress (Lemaire et al. 1999; Clinton et al. 2011).”

“…et al., 2007, 2010, 2011b; Turner et al., 2008, 2011; Stedenfeld et al., 2011), as well as responsivity to pharmacological and environmental interventions (Jama et al., 2008; Perez et al., 2009; Calvo et al., 2011; Clinton et al., 2011a; Turner et al., 2011; Aydin et al., 2015; Rana et al., 2015).”

“A detailed description of the breeding paradigm and characterization of these bred lines has been published previously (Stead et al., 2006, Flagel et al., 2010, Garcia-Fuster et al., 2010, Clinton et al., 2011).”

“Likewise, rodent research suggests that group level volumetric differences may change over time, although they may still be functionally significant (54).”

“…and molecular studies in the selectively bred HR/LR rats identified several differences in the HR versus LR hippocampus, including differences in cell proliferation, hippocampal volume, and gene expression (Clinton et al., 2011; Garcia-Fuster et al., 2010; Perez et al., 2009; Simmons et al., 2012).”

“…findings were evident primarily in males would be consistent with evidence, from lower organisms through rodents to humans, that exploratory drive is stronger in males, in a manner that involves hippocampal more than accumbal processes (Clinton et al, 2011; Cross et al, 2013; Videlier et al, 2015).”

“In order to study neurobiological factors that contribute to individual differences in emotional behavior, our laboratory has spent the last several years working with selectively bred lines of Sprague– Dawley rats that were bred based on differences in noveltyinduced exploratory behavior (Clinton et al., 2011; Cohen…”

“Similarly, selectively bred HR and LR (bHR/bLR) lines of Sprague-Dawley rats revealed, through Ki67 immunohistochemistry, enhanced cell proliferation in the DG of developing bLR versus bHR pups [40].”

“…in intercross animals (Hebda-Bauer et al., 2023) The consistency, stability and predictability of these bred phenotypes across generations (Clinton et al., 2011a; Turner et al., 2011), along with their innate differences in stress response (Clinton et al., 2014) and social behavior…”

“…bNELR rats, which are characterized by exaggerated anxiety and immobility (Kabbaj et al., 2000; White et al., 2007; Perez et al., 2009; Flagel et al., 2010; Clinton et al., 2011, 2008), depressive-like behavior, and stress vulnerability (Clinton et al., 2011; Stedenfeld et al., 2011;…”

“…showing selection signatures previously identified in the Lidia breed (Eusebi et al., 2018;, Eusebi et al., 2019); c) RNA-seq studies in rodents (Clinton et al., 2011;, Malki et al., 2014) and silver foxes (Kukekova et al., 2011, Kukekova et al., 2018); and d) genes identified in studies with…”

“largely shifted to murine models of human diseases in the hope (rather real) of finding therapy approaches [12,18,28,47].”

“While these strains feature similar behavioral profiles, as demonstrated by our present work as well as that of others (Burke et al., 2016; Clinton et al., 2011; Cohen et al., 2017; Nam et al., 2014; Prater et al., 2017; Stead et al., 2006; Stedenfeld et al., 2011), WKY and bLR rats do show…”

“Il9r is differentially expressed in the nucleus accumbens and hippocampus of High Responder (bHR) and Low Responder (bLR) rats that were selectively bred for exploratory locomotor behavior in a novel environment (Clinton et al. 2011).”

“, 2019); c) RNA-seq studies in rodents (Clinton et al., 2011; Malki et al. 2014) and silver foxes (Kukekova et al.”