Angiotensin II differentially affects hippocampal glial inflammatory markers in young adult male and female mice

Hypertension is a risk factor for neurodegenerative disorders involving inflammation and inflammatory cytokine-producing brain cells (microglia and astrocytes) in the hippocampus and medial prefrontal cortex (mPFC). Here we investigated the effect of slow-pressor angiotensin II (AngII) on gliosis in the hippocampus and mPFC of young adult (2-mo-old) male and female mice. In males, AngII induced hypertension, and this resulted in an increase in the density of the astrocyte marker glial fibrillary acidic protein (GFAP) in the subgranular hilus and a decrease in the density of the microglial marker ionized calcium binding adapter molecule (Iba-1) in the CA1 region. Females infused with AngII did not show hypertension but, significantly, showed alterations in hippocampal glial activation. Compared with vehicle, AngII-infused female mice had an increased density of Iba-1 in the dentate gyrus and CA2/3a region. Like males, females infused with AngII exhibited decreased Iba-1 in the CA1 region. Neither male nor female mice showed differences in GFAP or Iba-1 in the mPFC following AngII infusion. These results demonstrate that the hippocampus is particularly vulnerable to AngII in young adulthood. Differences in gonadal hormones or the sensitivity to AngII hypertension may account for divergences in GFAP and Iba-1 in males and females.

Hypertension is a significant risk factor for neurological disorders such as Alzheimer''s disease (AD) that are associated with neurodegeneration and cognitive decline (Daugherty 2021). Hypertension can develop during the life span yet is often studied at middle and late life. There is emerging evidence that hypertension is becoming more common in late adolescence and early adulthood (Azegami et al. 2021; Hamrahian and Falkner 2022). In addition, there is increasing awareness that the duration of hypertension can impact the onset of neural degeneration (Schaare et al. 2019; Yang et al. 2021) and cognitive dysfunction (Yaffe et al. 2014, 2021; Mahinrad et al. 2020; Zhou et al. 2022). Although the age of onset of hypertension may influence the trajectory of degenerative disease in later life, the effect of hypertension on brain health in young adult subjects is relatively underinvestigated.Hippocampal and medial prefrontal cortical pathology are commonly present in neurodegenerative diseases like AD (Belonwu et al. 2021). Structurally and functionally, both the hippocampus and mPFC also are compromised during hypertension (Raz et al. 2007; Gonzalez et al. 2015; Bu et al. 2018). In the hippocampus, hypertension is known to disrupt cerebrovascular function, promote inflammatory processes, and contribute to neuronal impairment and cognitive decline (Iulita et al. 2018). Although less studied than the hippocampus, the PFC is also compromised by hypertension (Raz et al. 2007; Bu et al. 2018; Wang et al. 2020).Microglia, the resident macrophages in the brain, have been implicated in inflammatory states, cognitive function (Cornell et al. 2022), and the brain''s response to hypertension (Calvillo et al. 2019; Li et al. 2020). An increase in the density of ionized calcium binding adapter molecule (Iba-1), a protein constitutively expressed in microglia and up-regulated when microglia enter an activated stage (Imai et al. 1996; Sasaki et al. 2001), is commonly reported in models of cognitive and neurodegenerative disorders (Prinz et al. 2021).In addition to microglia, astrocytes also have been implicated in the emergence of hippocampal and cortical dysfunction. Astrocytes play critical roles in blood–brain barrier (BBB) formation; brain metabolic, ion, and water homeostasis; neurotransmitter recycling; synapse formation; and neuroimmune signaling (Matias et al. 2019). In the context of insult, pathogen infection, or neurological disease, astrocytes undergo functionally complex reactive responses (Chiu et al. 2014; Giovannoni and Quintana 2020) that are associated with an increase in glial fibrillary acidic protein (GFAP) gene and protein expression (Crespo-Castrillo et al. 2020; Sofroniew 2020).To better understand the consequences of elevated blood pressure on the young adult brain, we conducted an exploratory investigation of the impact of hypertension on the expression of microglia and astrocyte markers—Iba-1 and GFAP, respectively—in the hippocampus and mPFC of male mice. Mice were exposed to angiotensin II (AngII) using the “slow-pressor” model (Dickinson and Lawrence 1963), which in males mimics the gradual rise in blood pressure and increase in sympathetic activation (Grassi and Ram 2016; Lerman et al. 2019) characteristic of essential hypertension (Lerman et al. 2019). Significantly, there is an important sex dimorphism in the risk for hypertension. Compared with men, women are protected from hypertension before middle age but become increasingly affected as they reach perimenopause, and intact young female rodents show a reduced sensitivity to AngII hypertension (Van Kempen et al. 2016). Similarly, there are sex differences in the incidence, progression, and severity of hypertension-associated neurodegenerative disease (Lopez-Lee et al. 2021). Furthermore, sex differences in glial function have also been documented within the context of neurodegenerative diseases (Kodama and Gan 2019; Biechele et al. 2020). Given this evidence, the effect of AngII on hippocampal and medial prefrontal cortical glial markers also was investigated in young intact female mice.     

Knowledge and judgments about events that occurred prior to birth: The measurement of the persistence of information

Data from five laboratories using five different techniques were reanalyzed to measure subjects’ knowledge of events that occurred over the past 70 years. Subjects were about 20 years of age, so the measures included events that extended up to 50 years before birth. The functions relating knowledge about the events to age do not decrease precipitously at birth but gradually drop to above-chance levels. Techniques usually used to study retention within the individual can be used to study the persistence of ideas and fashions within an age cohort in a culture.     

Cognitive processes in implicit attitude tasks: An experimental validation of the Trip Model

Implicit attitude tasks have become very popular in various areas of psychology. However, little is known about the cognitive processes they involve. To address this issue, we investigated the underlying processes of the Go/No‐go Association Task (GNAT), a go/no‐go variant of the well‐known Implicit Association Test (IAT). More precisely, we tested two alternative multinomial processing tree (MPT) models of GNAT performance, the Trip Model and the generalized Quad Model. Both models assume that GNAT performance is influenced not only by automatic associations but also by response biases and a controlled discrimination process. However, the two models differ with respect to an additional overcoming bias process. In contrast to the Quad Model, the Trip Model assumes that overcoming bias does not play a major role in GNAT performance. Instead, the Trip Model emphasizes the role of response biases. We report three experiments that demonstrate the validity of the Trip Model for GNAT data. Copyright © 2010 John Wiley & Sons, Ltd.     

How do I remember that I know you know that I know?

Communication is aided greatly when speakers and listeners take advantage of mutually shared knowledge (i.e., common ground). How such information is represented in memory is not well known. Using a neuropsychological-psycholinguistic approach to real-time language understanding, we investigated the ability to form and use common ground during conversation in memory-impaired participants with hippocampal amnesia. Analyses of amnesics' eye fixations as they interpreted their partner's utterances about a set of objects demonstrated successful use of common ground when the amnesics had immediate access to common-ground information, but dramatic failures when they did not. These findings indicate a clear role for declarative memory in maintenance of common-ground representations. Even when amnesics were successful, however, the eye movement record revealed subtle deficits in resolving potential ambiguity among competing intended referents; this finding suggests that declarative memory may be critical to more basic aspects of the on-line resolution of linguistic ambiguity.     

Differential predictability of four dimensions of affect intensity

Individual differences in affect intensity are typically assessed with the Affect Intensity Measure (AIM). Previous factor analyses suggest that the AIM is comprised of four weakly correlated factors: Positive Affectivity, Negative Reactivity, Negative Intensity and Positive Intensity or Serenity. However, little data exist to show whether its four factors relate to other measures differently enough to preclude use of the total scale score. The present study replicated the four-factor solution and found that subscales derived from the four factors correlated differently with criterion variables that assess personality domains, affective dispositions, and cognitive patterns that are associated with emotional reactions. The results show that use of the total AIM score can obscure relationships between specific features of affect intensity and other variables and suggest that researchers should examine the individual AIM subscales.     

Hindsight bias from 3 to 95 years of age

Upon learning the outcome to a problem, people tend to believe that they knew it all along (hindsight bias). Here, we report the first study to trace the development of hindsight bias across the life span. One hundred ninety-four participants aged 3 to 95 years completed 3 tasks designed to measure visual and verbal hindsight bias. All age groups demonstrated hindsight bias on all 3 tasks; however, preschoolers and older adults exhibited more bias than older children and younger adults. Multinomial processing tree analyses of these data revealed that preschoolers' enhanced hindsight bias resulted from them substituting the correct answer for their original answer in their recall (a qualitative error). Conversely, older adults' enhanced hindsight bias resulted from them forgetting their original answer and recalling an answer closer to, but not equal to, the correct answer (a quantitative error). We discuss these findings in relation to mechanisms of memory, perspective taking, theory of mind, and executive function.     

Callous-Unemotional Traits and Autonomic Functioning in Toddlerhood Interact to Predict Externalizing Behaviors in Preschool

Callous-unemotional (CU) traits are one meaningful risk factor which helps to explain heterogeneity in the emergence of externalizing behavior problems. While the extant literature demonstrates links between early CU traits and later externalizing problems, there is a dearth of research examining for whom early CU traits confer risk. Data from a longitudinal study (n?= 108) were used to examine the extent to which parasympathetic functioning moderated links between CU traits in toddlerhood (m _age ?=?24.99 months) and externalizing behavior problems at preschool-age (m _age ?=?51 months). Neither CU traits nor parasympathetic functioning at age 2 directly predicted later externalizing behaviors. However, results show that high levels of CU traits predict elevated externalizing behavior problems, but only for toddlers exhibiting either high baseline respiratory sinus arrhythmia (RSA) or little to no RSA suppression in response to a fear stimulus.