Neuregulin 1 gene and protein structures and the transcriptional start sites for type I and type III Nrg1 isoforms. A , The Nrg1 gene structure on mouse chromosome 8 (top) and the domain organization of three major types of Nrg1 proteins (bottom). Top, The colored blocks indicate individual exons. The approximate sizes of the introns are also indicated (not drawn to scale). All Nrg1 proteins share the EGF-like domain necessary for binding ErbB receptors. Each major type of Nrg1 protein is encoded by a distinct N-terminal exon: exon 2 (type I), exon 1 (type II), and exon 7 (type III), respectively. Three additional 5 Ј exons found in humans that encode type IV, V, and VI are shown as hatched boxes. C-terminal to the EGF domain, Nrg1 proteins either exist as soluble ( ␤ 3) or transmembrane proteins (the ␤ 1a variant is depicted). Nrg1 heterozygous mutant mice that are described in supplemental Table 2 (available at www.jneurosci.org as supplemental material) are labeled to indicate regions (isoforms) that are disrupted in each mutant mouse. S, Spacer; CRD, cysteine-rich domain; EGF, EGF-like domain; TM, transmembrane domain. B , Transcriptional start sites for type I and type III Nrg1 mRNA were identified by sequencing multiple PCR products amplified using a standard 5 Ј -RACE protocol. The identified 5 Ј ends of type I (left) and type III (right) transcripts are underlined and colored (red and blue, respectively). All type I products originated at nucleotide Ϫ 542 relative to the translational initiation codon in exon 2 (bold ATG). Four distinct 5 Ј ends for type III transcripts were identified 593, 705, 716, and 722 nt 5 Ј to the first coding ATG in exon 7 (the black letters indicate noncoding sequences, and the colored letters indicate coding sequences). The dashed lines with arrows pointing the orientation indicate primers (I-a, -b, -c; CRD-a, -b, -c) used in 5 Ј -RACE (see Materials and Methods). The sequence information is extracted from Celera locus cra_cmgc_G 307972 BP. 

Contexts in source publication

Context 1

... blood volume is decreased in the medial prefrontal cortex, CA1, and subiculum. Type III Nrg1 ϩ / Ϫ mice are impaired in a working/short-term memory task and have sensorimotor gating deficits. Chronic nicotine treatment increases PPI in type III Nrg1 ϩ / Ϫ mice. We demonstrate that reduction in type III Nrg1/ErbB signaling results in specific defects from the cellular level to behavioral tests of frontal and temporolimbic corticostriatal circuits. Such specificity is evident in each set of data. For example, there were decreased spine densities in the proximal apical dendrites of subicular pyramidal neurons in type III Nrg1 ϩ / Ϫ mice, but dendritic intersections, dendritic lengths, and distal spine densities were unchanged. This suggests that the effects of decreased type III Nrg1 may interact with synaptic contacts or other mechanisms that maintain spines of apical dendrites relatively proximal to the soma of subicular pyramidal neurons. The ventral subiculum serves as a major output pathway for cortical outputs of hippocampus (Naber et al., 2000; Witter, 2006). Neurons within the subiculum act as recipients and comparators re- ceiving signals from prefrontal association in the medial prefrontal cortices as well as thalamus (Lisman and subregions (marked and gyrus (DG), and the Grace, 2005). The proximal apical den- at the bottom panels. drites of subicular pyramidal neurons re- the rCBV for each region. B , ceive inputs from the CA1; the distal apical Ϫ ) with the hippocampal dendrites receive inputs from the entorhi- observed in the CA1 and nal cortex. Processed information is sent Basal measures of rCBV, a back from subicular pyramidal neurons to well as medial prefrontal the entorhinal cortex, medial prefrontal the CA1, subiculum, medial cortex, ventral striatum, and other limbic with their wild-type (blue) structures (Naber et al., 1999, 2000, 2001). Error bars indicate SEM. D , Interestingly, we found that functional ac- ϩ / Ϫ animals. tivity, as measured by rCBV, of CA1, subiculum, and the medial prefrontal cortex are coordinately downregulated in type III Nrg1 ϩ / Ϫ mice, whereas functional activity in the dentate gyrus, entorhinal cortex, ventral striatum (nucleus accumbens), and sensory/motor cortex are unchanged. The decreased functional profile is consistent with decreased spine density of the proximal regions of subicular pyramidal neurons (inputs from the CA1) and unchanged spine density in the distal regions (inputs from the entorhinal cortex) in type III Nrg1 ϩ / Ϫ mice and is in agreement activity (mean Ϯ with the expression pattern of type III Nrg1 stereotypy in a novel open as well as its requirement for proper senso- in general activity rimotor gating and short-term memory genotype ϭ 0.34). performance, both of which are sensitive to disruption in the prefrontal cortex and the ventral hippocampus (Caine et al., 1992; Lipska et al., 1995, 2002; Swerdlow et al., 1995; Moore et al., 2006). Polymorphisms in the Nrg1 gene are associated with psychiatric disorders, such as schizophrenia, bipolar disorder, and late- onset Alzheimer’s disease with psychosis (Stefansson et al., 2002; Go et al., 2005; Green et al., 2005; Harrison and Weinberger, 2005; Harrison and Law, 2006; Thomson et al., 2007). It has been proposed that altered expression of the NRG1 gene underlies the molecular mechanism by which polymorphisms in the NRG1 Glantz and Lewis, 2000; Rosoklija et al., 2000; Wright et al., 2000). Moreover, Nrg1 type III heterozygotes show impaired working memory and sensorimotor gating deficits, behavioral phenotypes associated with schizophrenia (Goldman-Rakic, 1999; Braff et al., 2001). Finally, high levels of cigarette smoking are prevalent in schizophrenics (Kumari and Postma, 2005; George et al., 2006), suggesting self-medication with nicotine (Kumari and Postma, 2005). Experimental administration of nicotine ameliorates working memory and PPI deficits in schizophrenia (Kumari and Postma, 2005; George et al., 2006; Postma et al., 2006). Thus, it is of interest that nicotine appears to normalize the PPI deficits in type III Nrg1 heterozygous mice. The relationships between allelic variation on the NRG1 gene and vulnerability to developing schizophrenia remain to be determined. We believe animal models have the potential to pro- vide important insights into how alterations in the Nrg1/ErbB expression are related to the cognitive and affective deficits char- acteristic of schizophrenia. Several different Nrg1 mutant mice have been studied behaviorally (supplemental Table 2, available at www.jneurosci.org as supplemental material). These include type III Nrg1 specific mutants (Wolpowitz et al., 2000; this study), type I/type II mutants (generated by disruption of the Ig domains) (Kramer et al., 1996), transmembrane domain-deleted mutants (which affect types I, II, and III) (Stefansson et al., 2002), and pan-Nrg1 mutants (generated by deletion of EGF-like domain) (Meyer and Birchmeier, 1995) (Fig. 1). In behavioral analyses, TM-Nrg1 ϩ / Ϫ and EGF-Nrg1 ϩ / Ϫ mice were hyperactive in the novel open-field assay (Gerlai et al., 2000; Stefansson et al., 2002; Karl et al., 2007). In contrast, Ig-Nrg1 ϩ / Ϫ and CRD-Nrg1 ϩ / Ϫ mice exhibit normal locomotor activity compared with wild-type controls (Rimer et al., 2005). TM-Nrg1 ϩ / Ϫ mice have weak PPI deficits, whereas CRD-Nrg1 ϩ / Ϫ mice have strong PPI deficits (Stefansson et al., 2002). CRD-Nrg1 ϩ / Ϫ mice have impaired performance in a short-term memory/working memory test, whereas TM-Nrg1 ϩ / Ϫ mice are unaffected in a spatial working memory test (O’Tuathaigh et al., 2007a). TM- Nrg1 ϩ / Ϫ mice are more aggressive toward an intruder mouse in the resident–intruder paradigm (O’Tuathaigh et al., 2007a); a behavior not seen in CRD-Nrg1 ϩ / Ϫ mice (Y.-J. Chen, D. A. Talmage, and L. W. Role, unpublished observation). Although some aspects of behavioral phenotypes in different Nrg1 isoform mutant mice are yet to be determined (supplemental Table 2, available at www.jneurosci.org as supplemental material), these distinct behavioral phenotypes are likely to reflect both differences in expression patterns, as well as distinct functional properties of different Nrg1 isoforms, as has been demon- strated in studies of myelination (supplemental Table 2, available at www.jneurosci.org as supplemental material) (Michailov et al., 2004; Taveggia et al., 2005; S. Chen et al., 2006). Resolution of the differences in the profiles of behavioral abnormalities in the Nrg1 mutant mice awaits detailed morphological, cellular, and physiological analyses of the underlying circuits. These data, considered in the context of the other reports, broaden our understanding of Nrg1 in general and of the physiological functions of type III Nrg1, in particular. Normal levels of type III Nrg1 are required for normal corticolimbic circuits: decreased expression of type III Nrg1 leads to structural, functional, and behavioral alterations that are related to schizophrenia. More in-depth studies of Nrg1/ErbB signaling in type III Nrg1 ϩ / Ϫ mice are needed to unravel the causal factors leading to schizophrenia susceptibility and to provide novel therapeutics for disease ...

Context 2

... Nrg1 gene encodes three major groups of isoforms that are defined by their first coding exon ( Fig. 1 A ) (Falls, 2003). Type I Nrg1 and type II Nrg1 both contain an Ig domain N-terminal to the EGF domain, whereas type III Nrg1 contains a cysteine-rich domain N-terminal to the EGF-like domain. Genetic and cell biological studies reveal that different Nrg1 isoforms play discrete and sometimes complementary roles in neural development (Meyer et al., 1997; Wolpowitz et al., 2000; Falls, 2003; Flames et al., 2004; Michailov et al., 2004; Taveggia et al., 2005; Lopez- Bendito et al., 2006). Generation of multiple isoforms of Nrg1 likely results from a combination of differential promoter usage and alternative splicing (Falls, 2003). To investigate the molecu- lar mechanisms regulating the expression patterns of type III- versus type I-containing Nrg1 isoforms, we asked whether distinct promoters control Nrg1 transcription. 5 Ј -RACE identified multiple transcriptional start sites continuous with, and within 1 kb of the type III Nrg1 coding region (Fig. 1 B ), indicating that a unique type III Nrg1 core promoter lies immediately adjacent to the first exon of type III Nrg1. The importance of type III Nrg1 in the nervous system is supported by studies of isoform-specific knock-out mice (Wolpowitz et al., 2000; Bao et al., 2003; Flames et al., 2004; Michailov et al., 2004; Taveggia et al., 2005; Lopez-Bendito et al., 2006). To investigate roles of type III Nrg1 in postnatal brain development, we examined RNA expression of type III Nrg1 and one of its receptors, ErbB4 in mice. Type III Nrg1 mRNA is expressed in medial prefrontal cortex and hippocampus (Fig. 2 B , C , E , F ), areas associated with attention, executive function, and memory (Naber et al., 2000; Vinogradova, 2001; Dalley et al., 2004). In the medial prefrontal cortex, type III Nrg1 is highly expressed in layer 5 in the cingulate cortex, prelimbic, and infralimbic cortices (Fig. 2 B , C ). In the hippocampus, type III Nrg1 is predominantly seen in the CA3 and the subiculum (Fig. 2 E , F ). Fewer cells are positive for type III Nrg1 mRNA in the CA1 region, although the strength of expression is high (Fig. 2 E ). ErbB4 expression is detected in projection fields of the prefrontal cortex and ventral hippocampus, including the ventral striatum (Fig. 2 G ). As such, Nrg1/ ErbB4 signaling might be required for the maintenance of normal cortical and hippocampal structures and may influence corticolimbic circuits and related behaviors. To investigate the possible role of type III Nrg1 in adult brain organization and in the performance of specific behaviors, we compared adult type III Nrg1 heterozygous mutant mice ( ϩ / Ϫ ) with wild-type ( ϩ / ϩ ) siblings [the homozygous mutants die at birth (Wolpowitz et al., 2000)]. Examining overall anterior brain morphology in coronal sections from ϩ / ϩ and ϩ / Ϫ sibling pairs revealed enlarged lateral ventricles in ϩ / Ϫ animals. Serial sections were aligned by major landmarks [e.g., genu of the corpus callosum (cc); anterior commissure (ac)] (Fig. 3 A ) to permit comparisons between genotypes of the area indicated in Figure 3 A . Starting with sections at the most anterior limb of the corpus callosum (section S1) to sections including the hippocampal formation (section S10), the lateral ventricular volume of ϩ / Ϫ mice ranged from 1.2 to 25 times larger than in comparable sections from ϩ / ϩ littermates (Fig. 3 B , C ). Analysis of age-matched animals revealed statistically significant differences in total LV volume between ϩ / ϩ and ϩ / Ϫ animals (Fig. 3 D ) ( n ϭ 13 ϩ / ϩ vs 18 ϩ / Ϫ ; p Ͻ 0.02). Thus, reduced type III Nrg1 signaling has a significant effect on gross morphology of adult brains, an effect that is more pronounced in older animals (Fig. 3 D ). Nrg1/ErbB signaling contributes to synaptic plasticity and maturation at glutamatergic synapses (Bao et al., 2004; Li et al., 2007). Acute treatment with Nrg1 protein induces neurite out- growth, extension, and branching in hippocampal neurons in vitro (Gerecke et al., 2004). Knockdown of ErbB4 with RNA in- terference in CA1 pyramidal neurons leads to decreased dendritic spine density in the CA1 pyramidal neurons (Li et al., 2007). The abundant expression of type III Nrg1 in the subicular region suggests a possible role in the synaptic plasticity of pyramidal neurons, in which proper dendritic arborization and spine density are required for accurate integration and processing of the convergent information from the hippocampus and extrahip- pocampal inputs. To analyze the dendritic spine density of subicular pyramidal neurons, brains from five pairs of ϩ / ϩ and type III Nrg1 ϩ / Ϫ sibling mice were processed with modified Golgi methods (see Materials and Methods). We focused our analysis on coronal sections containing the ventral subiculum, where type III Nrg1 is highly expressed (Fig. 4 A ). The entire dendritic field (branches and spines on the apical dendrites and basilar dendrites) of individual, randomly chosen pyramidal neurons ( n ϭ 30 neurons for ϩ / ϩ ; n ϭ 44 neurons for ϩ / Ϫ ) from the inner layer of the subiculum were traced and analyzed. Two representative tracings of ϩ / ϩ and ϩ / Ϫ neurons are shown in Figure 4 B . Compared with their ϩ / ϩ littermates, type III Nrg1 ϩ / Ϫ mice have significantly lower spine densities within the proximal apical dendrites of the pyramidal neurons ( ϳ 50 –210 ␮ m from the center of the soma) (Fig. 4 C , D ). Nonparametric Kolmogorov–Smirnov test using genotype as an independent variable and averaged apical spine density as an dependent variable revealed significant difference between genotype ( ␹ 2 ϭ 48.9; p genotype Ͻ 0.0001). The difference in spine density was significant along multiple 10 ␮ m bins (K–S test: p Ͻ 0.05 at 50, 80, 140, 180, 190, 200, and 270; p Ͻ 0.01 at 70, 100, 150, 170, and 230) (Fig. 4 D ). Similarly, the spine density on the basilar dendrites of pyramidal neurons was lower from 40 to 100 ␮ m away from the soma in type III Nrg1 ϩ / Ϫ than in ϩ / ϩ mice, although none of the 10 ␮ m bins reached statistical significance (data not shown). There were no statisti- cally significant differences in dendritic intersections or dendritic lengths between genotypes (data not shown). Dendritic spines are the sites of most excitatory synaptic inputs and are known to be formed or eliminated in response to sensory experiences and neural activities (Engert and Bonhoeffer, 1999; Zuo et al., 2005; Holtmaat et al., 2006; Sheng and Hoogenraad, 2007). To determine whether structural alterations in hippocampal pyramidal neurons are translated into functional alterations, we compared rCBV, an indicator of brain metabolism and neuronal function (Gonzalez et al., 1995; van Zijl et al., 1998; Small, 2003), of type III Nrg1 ϩ / Ϫ mice versus ϩ / ϩ controls ( n ϭ 6 ϩ / ϩ vs 9 ϩ / Ϫ ) (Fig. 5 A–D ). Compared with ϩ / ϩ littermates, type III Nrg1 ϩ / Ϫ mice have significantly lower rCBV in CA3, CA1, and the subiculum of the hippocampus (Fig. 5 B , C ) (differences between genotype using ANOVA test: SUB, F ϭ 16.2, p Ͻ 0.002; CA1, F ϭ 8.5, p Ͻ 0.02; CA3, F ϭ 5.4, p Ͻ 0.04). The functional activity of the dentate gyrus and the entorhinal cortex, major input pathways to the hippocampal trisynaptic circuit, were not significantly different between genotypes (Fig. 5 B , C ) (differences between genotype using ANOVA test: entorhinal cortex, F ϭ 1.7, p ϭ 0.21; DG, F ϭ 2.4, p ϭ 0.15). Medial prefrontal cortex (medial orbital cortex, prelimbic cortex, and a frac- tion of the infralimbic cortex) as well as the ventral striatum (nucleus accumbens) receive inputs from CA1 and the ...

Context 3

... Nrg1 gene encodes three major groups of isoforms that are defined by their first coding exon ( Fig. 1 A ) (Falls, 2003). Type I Nrg1 and type II Nrg1 both contain an Ig domain N-terminal to the EGF domain, whereas type III Nrg1 contains a cysteine-rich domain N-terminal to the EGF-like domain. Genetic and cell biological studies reveal that different Nrg1 isoforms play discrete and sometimes complementary roles in neural development (Meyer et al., 1997; Wolpowitz et al., 2000; Falls, 2003; Flames et al., 2004; Michailov et al., 2004; Taveggia et al., 2005; Lopez- Bendito et al., 2006). Generation of multiple isoforms of Nrg1 likely results from a combination of differential promoter usage and alternative splicing (Falls, 2003). To investigate the molecu- lar mechanisms regulating the expression patterns of type III- versus type I-containing Nrg1 isoforms, we asked whether distinct promoters control Nrg1 transcription. 5 Ј -RACE identified multiple transcriptional start sites continuous with, and within 1 kb of the type III Nrg1 coding region (Fig. 1 B ), indicating that a unique type III Nrg1 core promoter lies immediately adjacent to the first exon of type III Nrg1. The importance of type III Nrg1 in the nervous system is supported by studies of isoform-specific knock-out mice (Wolpowitz et al., 2000; Bao et al., 2003; Flames et al., 2004; Michailov et al., 2004; Taveggia et al., 2005; Lopez-Bendito et al., 2006). To investigate roles of type III Nrg1 in postnatal brain development, we examined RNA expression of type III Nrg1 and one of its receptors, ErbB4 in mice. Type III Nrg1 mRNA is expressed in medial prefrontal cortex and hippocampus (Fig. 2 B , C , E , F ), areas associated with attention, executive function, and memory (Naber et al., 2000; Vinogradova, 2001; Dalley et al., 2004). In the medial prefrontal cortex, type III Nrg1 is highly expressed in layer 5 in the cingulate cortex, prelimbic, and infralimbic cortices (Fig. 2 B , C ). In the hippocampus, type III Nrg1 is predominantly seen in the CA3 and the subiculum (Fig. 2 E , F ). Fewer cells are positive for type III Nrg1 mRNA in the CA1 region, although the strength of expression is high (Fig. 2 E ). ErbB4 expression is detected in projection fields of the prefrontal cortex and ventral hippocampus, including the ventral striatum (Fig. 2 G ). As such, Nrg1/ ErbB4 signaling might be required for the maintenance of normal cortical and hippocampal structures and may influence corticolimbic circuits and related behaviors. To investigate the possible role of type III Nrg1 in adult brain organization and in the performance of specific behaviors, we compared adult type III Nrg1 heterozygous mutant mice ( ϩ / Ϫ ) with wild-type ( ϩ / ϩ ) siblings [the homozygous mutants die at birth (Wolpowitz et al., 2000)]. Examining overall anterior brain morphology in coronal sections from ϩ / ϩ and ϩ / Ϫ sibling pairs revealed enlarged lateral ventricles in ϩ / Ϫ animals. Serial sections were aligned by major landmarks [e.g., genu of the corpus callosum (cc); anterior commissure (ac)] (Fig. 3 A ) to permit comparisons between genotypes of the area indicated in Figure 3 A . Starting with sections at the most anterior limb of the corpus callosum (section S1) to sections including the hippocampal formation (section S10), the lateral ventricular volume of ϩ / Ϫ mice ranged from 1.2 to 25 times larger than in comparable sections from ϩ / ϩ littermates (Fig. 3 B , C ). Analysis of age-matched animals revealed statistically significant differences in total LV volume between ϩ / ϩ and ϩ / Ϫ animals (Fig. 3 D ) ( n ϭ 13 ϩ / ϩ vs 18 ϩ / Ϫ ; p Ͻ 0.02). Thus, reduced type III Nrg1 signaling has a significant effect on gross morphology of adult brains, an effect that is more pronounced in older animals (Fig. 3 D ). Nrg1/ErbB signaling contributes to synaptic plasticity and maturation at glutamatergic synapses (Bao et al., 2004; Li et al., 2007). Acute treatment with Nrg1 protein induces neurite out- growth, extension, and branching in hippocampal neurons in vitro (Gerecke et al., 2004). Knockdown of ErbB4 with RNA in- terference in CA1 pyramidal neurons leads to decreased dendritic spine density in the CA1 pyramidal neurons (Li et al., 2007). The abundant expression of type III Nrg1 in the subicular region suggests a possible role in the synaptic plasticity of pyramidal neurons, in which proper dendritic arborization and spine density are required for accurate integration and processing of the convergent information from the hippocampus and extrahip- pocampal inputs. To analyze the dendritic spine density of subicular pyramidal neurons, brains from five pairs of ϩ / ϩ and type III Nrg1 ϩ / Ϫ sibling mice were processed with modified Golgi methods (see Materials and Methods). We focused our analysis on coronal sections containing the ventral subiculum, where type III Nrg1 is highly expressed (Fig. 4 A ). The entire dendritic field (branches and spines on the apical dendrites and basilar dendrites) of individual, randomly chosen pyramidal neurons ( n ϭ 30 neurons for ϩ / ϩ ; n ϭ 44 neurons for ϩ / Ϫ ) from the inner layer of the subiculum were traced and analyzed. Two representative tracings of ϩ / ϩ and ϩ / Ϫ neurons are shown in Figure 4 B . Compared with their ϩ / ϩ littermates, type III Nrg1 ϩ / Ϫ mice have significantly lower spine densities within the proximal apical dendrites of the pyramidal neurons ( ϳ 50 –210 ␮ m from the center of the soma) (Fig. 4 C , D ). Nonparametric Kolmogorov–Smirnov test using genotype as an independent variable and averaged apical spine density as an dependent variable revealed significant difference between genotype ( ␹ 2 ϭ 48.9; p genotype Ͻ 0.0001). The difference in spine density was significant along multiple 10 ␮ m bins (K–S test: p Ͻ 0.05 at 50, 80, 140, 180, 190, 200, and 270; p Ͻ 0.01 at 70, 100, 150, 170, and 230) (Fig. 4 D ). Similarly, the spine density on the basilar dendrites of pyramidal neurons was lower from 40 to 100 ␮ m away from the soma in type III Nrg1 ϩ / Ϫ than in ϩ / ϩ mice, although none of the 10 ␮ m bins reached statistical significance (data not shown). There were no statisti- cally significant differences in dendritic intersections or dendritic lengths between genotypes (data not shown). Dendritic spines are the sites of most excitatory synaptic inputs and are known to be formed or eliminated in response to sensory experiences and neural activities (Engert and Bonhoeffer, 1999; Zuo et al., 2005; Holtmaat et al., 2006; Sheng and Hoogenraad, 2007). To determine whether structural alterations in hippocampal pyramidal neurons are translated into functional alterations, we compared rCBV, an indicator of brain metabolism and neuronal function (Gonzalez et al., 1995; van Zijl et al., 1998; Small, 2003), of type III Nrg1 ϩ / Ϫ mice versus ϩ / ϩ controls ( n ϭ 6 ϩ / ϩ vs 9 ϩ / Ϫ ) (Fig. 5 A–D ). Compared with ϩ / ϩ littermates, type III Nrg1 ϩ / Ϫ mice have significantly lower rCBV in CA3, CA1, and the subiculum of the hippocampus (Fig. 5 B , C ) (differences between genotype using ANOVA test: SUB, F ϭ 16.2, p Ͻ 0.002; CA1, F ϭ 8.5, p Ͻ 0.02; CA3, F ϭ 5.4, p Ͻ 0.04). The functional activity of the dentate gyrus and the entorhinal cortex, major input pathways to the hippocampal trisynaptic circuit, were not significantly different between genotypes (Fig. 5 B , C ) (differences between genotype using ANOVA test: entorhinal cortex, F ϭ 1.7, p ϭ 0.21; DG, F ϭ 2.4, p ϭ 0.15). Medial prefrontal cortex (medial orbital cortex, prelimbic cortex, and a frac- tion of the infralimbic cortex) as well as the ventral striatum (nucleus accumbens) receive inputs from CA1 and the ...