Notch in memories: Points to remember

Memory is a temporally evolving molecular and structural process, which involves changes from local synapses to complex neural networks. There is increasing evidence for an involvement of developmental pathways in regulating synaptic communication in the adult nervous system. Notch signaling has been implicated in memory formation in a variety of species. Nevertheless, the mechanism of Notch underlying memory consolidation remains poorly understood. In this commentary, besides offering an overview of the advances in the field of Notch in memory, we highlight some of the weaknesses of the studies and attempt to cast light on the apparent discrepancies on the role of Notch in memory. We believe that future studies, employing high‐throughput technologies and targeted Notch loss and gain of function animal models, will reveal the mechanisms of Notch dependent plasticity and resolve whether this signaling pathway is implicated in the cognitive deficit associated with dementia. © 2015 Wiley Periodicals, Inc.     

Cueing the personal future to reduce discounting in intertemporal choice: Is episodic prospection necessary?

How does the ability to imagine detailed future experiences (i.e., episodic prospection) contribute to choices between immediate and delayed rewards? Individuals with amnesia do not show abnormally steep discounting in intertemporal choice, suggesting that neither medial temporal lobe (MTL) integrity nor episodic prospection is required for the valuation of future rewards (Kwan et al. ( ), Hippocampus, 22:1215‐1219; Kwan et al. (2013), J Exp Psychol, 142:1355‐1369 2013). However, hippocampally mediated episodic prospection in healthy adults reduces the discounting of future rewards (Peters and Büchel (2010), Neuron, 66:138‐148; Benoit et al. (2011), J Neurosci, 31:6771‐6779), raising the possibility that MTL damage causes more subtle impairments to this form of decision‐making than noted in previous patient studies. Intertemporal choice appears normal in amnesic populations, yet they may be unable to use episodic prospection to adaptively modulate the value assigned to future rewards. To investigate how the extended hippocampal system, including the hippocampus and related MTL structures, contributes to the valuation of future rewards, we compared the performance of six amnesic cases with impaired episodic prospection to that of 20 control participants on two versions of an intertemporal choice task: a standard discounting task, and a cued version in which cues prompted them to imagine specific personal future events temporally contiguous with the receipt of delayed rewards. Amnesic individuals' intertemporal choices in the standard condition were indistinguishable from those of controls, replicating previous findings. Surprisingly, performance of the amnesic cases in the cued condition indicates that amnesia does not preclude flexible modulation of choices in response to future event cues, even in the absence of episodic prospection. Cueing the personal future to modulate decisions appears to constitute a less demanding or a qualitatively different (e.g., personal semantic) form of prospection that is not as sensitive to MTL damage as prospective narrative generation. © 2015 Wiley Periodicals, Inc.     

Cux2 activity defines a subpopulation of perinatal neurogenic progenitors in the hippocampus

The hippocampus arises from the medial region of the subventricular (SVZ) within the telencephalon. It is one of two regions in the postnatal brain that harbors neural progenitors (NPs) capable of giving rise to new neurons. Neurogenesis in the hippocampus is restricted to the subgranular zone (SGZ) of the dentate gyrus (DG) where it contributes to the generation of granule cell layer (gcl) neurons. It is thought that SGZ progenitors are heterogeneous, differing in their morphology, expression profiles, and developmental potential, however it is currently unknown whether they display differences in their developmental origins and cell fate‐restriction in the DG. Here we demonstrate that Cux2 is a marker for SGZ progenitors and nascent granule cell neurons in the perinatal brain. Cux2 was expressed in the presumptive hippocampal forming region of the embryonic forebrain from E14.5 onwards. At fetal stages, Cux2 was expressed in early‐forming Prox1⁺ granule cell neurons as well as the SVZ of the DG germinal matrix. In the postnatal brain, Cux2 was expressed in several types of progenitors in the SGZ of the DG, including Nestin/Sox2 double‐positive radial glia, Sox2⁺ cells that lacked a radial glial process, DCX⁺ neuroblasts, and Calretinin‐expressing nascent neurons. Another domain characterized by a low level of Cux2 expression emerged in Calbindin⁺ neurons of the developing DG blades. We used Cux2‐Cre mice in genetic fate‐mapping studies and showed almost exclusive labeling of Calbindin‐positive gcl neurons, but not in any progenitor cell types or astroglia. This suggests that Cux2⁺ progenitors directly differentiate into gcl neurons and do not self‐renew. Interestingly, developmental profiling of cell fate revealed an outside‐in formation of gcl neurons in the DG, likely reflecting the activity of Cux2 in the germinative matrices during DG formation and maturation. However, DG morphogenesis proceeded largely normally in hypomorphic Cux2 mutants lacking Cux2 expression. Taken together we conclude that Cux2 expression reflects hippocampal neurogenesis and identifies non‐self‐renewing NPs in the SGZ. © 2014 The Authors Hippocampus Published by Wiley Periodicals, Inc.     

The medial temporal lobes are critical for reward‐based decision making under conditions that promote episodic future thinking

In the present study, we investigated the effect of medial temporal lobe (MTL) damage on human decision making in the context of reward‐based intertemporal choice. During intertemporal choice, humans typically devalue (or discount) a future reward to account for its delayed arrival (e.g., preferring $30 now over $42 in 2 months), but this effect is attenuated when participants engage in episodic future thinking, i.e., project themselves into the future to imagine a specific event. We hypothesized that this attenuation would be selectively impaired in amnesic patients, who have deficits in episodic future thinking. Replicating previous work, in a standard intertemporal choice task, amnesic patients showed temporal discounting indices similar to healthy controls. Consistent with our hypothesis, while healthy controls demonstrated attenuated temporal discounting in a condition that required participants first to engage in episodic future thinking (e.g., to imagine spending $42 at a theatre in 2 months), amnesic patients failed to demonstrate this effect. Moreover, as expected, amnesic patients' narratives were less episodically rich than those of controls. These findings extend the range of tasks that are shown to be MTL dependent to include not only memory‐based decision‐making tasks but also future‐oriented ones. © 2014 Wiley Periodicals, Inc.     

Posterior compensatory network in cognitively intact elders with hippocampal atrophy

Functional compensation in late life is poorly understood but may be vital to understanding long‐term cognitive trajectories. To study this we first established an empirically derived threshold to distinguish hippocampal atrophy in those with Mild Cognitive Impairment (MCI n = 34) from those with proficient cognition (PRO n = 22), using data from a population‐based cohort. Next, to identify compensatory networks we compared cortical activity patterns during a graded spatial working memory (SWM) task in only cognitively proficient individuals, either with (PRO_ATR) or without hippocampal atrophy (PRO_NIL). Multivariate Partial Least Squares analyses revealed that these groups engaged spatially distinct SWM‐related networks. In those with hippocampal atrophy and under conditions of basic‐SWM demand, expression of a posterior compensatory network (PCN) comprised calcarine and posterior parietal cortex strongly correlated with superior SWM performance (r = −0.96). In these individuals, basic level SWM response times were faster and no less accurate than in those with no hippocampal atrophy. Cognitively proficient older individuals with hippocampal atrophy may, therefore, uniquely engage posterior brain areas when performing simple spatial working memory tasks. © 2014 Wiley Periodicals, Inc.     

Contribution of estrogen receptor subtypes,ERα, ERβ, and GPER1 in rapid estradiol‐mediated enhancement of hippocampal synaptic transmission in mice

Estradiol rapidly modulates hippocampal synaptic plasticity and synaptic transmission; however, the contribution of the various estrogen receptors to rapid changes in synaptic function is unclear. This study examined the effect of estrogen receptor selective agonists on hippocampal synaptic transmission in slices obtained from 3–5‐month‐old wild type (WT), estrogen receptor alpha (ERαKO), and beta (ERβKO) knockout female ovariectomized mice. Hippocampal slices were prepared 10–16 days following ovariectomy and extracellular excitatory postsynaptic field potentials were recorded from CA3‐CA1 synaptic contacts before and following application of 17β‐estradiol‐3‐benzoate (EB, 100 pM), the G‐protein estrogen receptor 1 (GPER1) agonist G1 (100 nM), the ERα selective agonist propyl pyrazole triol (PPT, 100 nM), or the ERβ selective agonist diarylpropionitrile (DPN, 1 µM). Across all groups, EB and G1 increased the synaptic response to a similar extent. Furthermore, prior G1 application occluded the EB‐mediated enhancement of the synaptic response and the GPER1 antagonist, G15 (100 nM), inhibited the enhancement of the synaptic response induced by EB application. We confirmed that the ERα and ERβ selective agonists (PPT and DPN) had effects on synaptic responses specific to animals that expressed the relevant receptor; however, PPT and DPN produced only a small increase in synaptic transmission relative to EB or the GPER1 agonist. We demonstrate that the increase in synaptic transmission is blocked by inhibition of extracellular signal‐regulated kinase (ERK) activity. Furthermore, EB was able to increase ERK activity regardless of genotype. These results suggest that ERK activation and enhancement of synaptic transmission by EB involves multiple estrogen receptor subtypes. © 2015 Wiley Periodicals, Inc.     

Obituary: Cornelius H. Vanderwolf

C.H. Vanderwolf described motor correlates of hippocampal theta oscillations and uncovered two broad classes: atropine‐sensitive and atropine‐resistant rhythm with likely different behavioral and cognitive significance. © 2015 Wiley Periodicals, Inc.     

Sociality and the telencephalic distribution of corticotrophin‐releasing factor,urocortin 3, and binding sites for CRF type 1 and type 2 receptors: A comparative study of eusocial naked mole‐rats and solitary Cape mole‐rats

Various aspects of social behavior are influenced by the highly conserved corticotrophin‐releasing factor (CRF) family of peptides and receptors in the mammalian telencephalon. This study has mapped and compared the telencephalic distribution of the CRF receptors, CRF₁ and CRF₂, and two of their ligands, CRF and urocortin 3, respectively, in African mole‐rat species with diametrically opposed social behavior. Naked mole‐rats live in large eusocial colonies that are characterized by exceptional levels of social cohesion, tolerance, and cooperation in burrowing, foraging, defense, and alloparental care for the offspring of the single reproductive female. Cape mole‐rats are solitary; they tolerate conspecifics only fleetingly during the breeding season. The telencephalic sites at which the level of CRF₁ binding in naked mole‐rats exceeds that in Cape mole‐rats include the basolateral amygdaloid nucleus, hippocampal CA3 subfield, and dentate gyrus; in contrast, the level is greater in Cape mole‐rats in the shell of the nucleus accumbens and medial habenular nucleus. For CRF₂ binding, the sites with a greater level in naked mole‐rats include the basolateral amygdaloid nucleus and dentate gyrus, but the septohippocampal nucleus, lateral septal nuclei, amygdalostriatal transition area, bed nucleus of the stria terminalis, and medial habenular nucleus display a greater level in Cape mole‐rats. The results are discussed with reference to neuroanatomical and behavioral studies of various species, including monogamous and promiscuous voles. By analogy with findings in those species, we speculate that the abundance of CRF₁ binding in the nucleus accumbens of Cape mole‐rats reflects their lack of affiliative behavior. J. Comp. Neurol. 523:2344–2371, 2015. © 2015 Wiley Periodicals, Inc.