Posterior parietal cortex oscillatory activity shapes persistent spatial memory impairments induced by soluble amyloid-β oligomers

doi:10.21203/rs.3.rs-3791891/v1

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Posterior parietal cortex oscillatory activity shapes persistent spatial memory impairments induced by soluble amyloid-β oligomers

https://doi.org/10.21203/rs.3.rs-3791891/v1

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Background: In early stages of Alzheimer's disease (AD), soluble amyloid-β (Aβ) is a key player disrupting neuronal activity and contributing to cognitive decline in advanced stages of the disease. While the hippocampus has been a central focus in prior research due to its susceptibility to Aβ-induced alterations, a comprehensive understanding of early AD pathology requires exploring interconnected brain regions. The posterior parietal cortex (PPC), collaborating closely with the hippocampus and involved in various memory processes, particularly spatial memory formation, holds particular significance. Investigating the PPC's function is imperative, as it may contribute to early AD characteristics and provide a more holistic perspective on disease progression.

Methods: To address this gap, we examined the relationship between neural oscillations and memory processes in the PPC and hippocampus in a mouse model of early hippocampal amyloidosis generated by intracerebroventricular oligomeric Aβ_1-42 (oAβ_1‑42) injections by performing in vivo oscillatory activity recordings from these regions in alert animals, together with spatial and habituation memory tests (Barnes maze and open field habituation).

Results: We found oAβ_1-42 to induce significant alterations in PPC oscillatory activity emerging several days after hippocampal disturbances showed by aberrant long-term potentiation (LTP) and network activity. Additionally, non-significant alterations of stereotyped behaviors were found.

Conclusions: Our results indicate that these atypical patterns provide insight into the persistent spatial memory deficits observed in our amyloidosis model and the temporal progression of the deleterious effects caused by Aβ. Furthermore, they support the potential use of PPC oscillatory activity as a valuable tool for early detection and intervention in AD.

Alzheimer’s disease

oligomers

amyloid-β

spatial memory

posterior parietal cortex

hippocampus

oscillatory activity.

The posterior parietal cortex (PPC) is an associative cortical area situated in the posterior segment of the parietal lobe. It functions as a hub for processing sensory inputs, particularly from somatic and visual regions, synthesizing this information to construct a representation of the body’s position in space [1, 2]. Traditionally, the PPC has been liked to various cognitive functions, encompassing visual perception, spatial attention, and visual guidance [3]. This area can be further dissected into two primary subregions: the dorsal PPC (dPPC), implicated in top–down attention driven by internal goals, and the ventral PPC (vPPC), mediating bottom–up, stimulus-driven attention [4, 5].

Recent studies have unveiled the PPC’s role in episodic memory encoding and retrieval, both in humans and rodents [3, 6-8]. Traditionally, these functions have been ascribed to the hippocampus [9], but PPC lesions in patients result in anterograde and retrograde memory deficits [10]. Successful episodic memory formation and recall require a delicate interplay between the emergence of stored memory traces, overseen by the hippocampus, and the top–down control based on retrieval goals, attributed to the prefrontal cortex [11]. Through its connections to these areas, the PPC appears to play a pivotal role in episodic memory retrieval and updating, influencing new memories based on current experiences [12-14]. Furthermore, functional magnetic resonance imaging (fMRI) studies have revealed a positive correlation between the strength of the functional connectivity between the PPC and the hippocampus, and spatial memory performance accuracy [15]. Specifically, the dPPC connects with the anterior hippocampus in humans (equivalent to the ventral hippocampus in rodents), while the vPPC is linked to the posterior (dorsal in rodents) hippocampus.

In this context, effective communication between the hippocampus and cortical regions, and modulation of these memory processes, rely on neural oscillations, particularly theta and gamma rhythms, and the degree of synchronization between these regions, known as inter-regional coherence [16-18]. Consequently, abnormal oscillatory activity could contribute to the pathophysiology of neurological and neurodegenerative diseases [19, 20].

Understanding the relationship between the PPC, the hippocampus, and memory has significant implications for neurodegenerative diseases such as Alzheimer's disease (AD) [21]. AD is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) senile plaques and neurofibrillary tangles in the brain, ultimately leading to neuronal dysfunction and cell death [22]. Memory impairment is a hallmark symptom of AD, with the hippocampus being one of the earliest affected areas [23]. Previous investigations focused on unravelling the initial phases of AD have highlighted that soluble Aβ species detrimentally affect hippocampal oscillatory activity, contributing to cognitive deficits alongside alterations in synaptic plasticity [24]. In the context of the PPC, investigations have shown that patients with mild cognitive impairment (MCI), a pre-AD stage, exhibit grey matter loss in this area compared to healthy subjects [2]. Additionally, significantly reduced connectivity between the PPC and the hippocampus has been observed in both MCI and early stages of AD [25, 26]. Consequently, dysfunction within the PPC-hippocampus network may serve as an early marker of AD pathology.

Nonetheless, the potential alterations in cortical oscillatory activity during the early stages of AD and its relationship with hippocampal neuronal activity remain largely unexplored. Therefore, this study aims to examine how early acute amyloidosis impacts the oscillatory activity of both the hippocampus and the PPC, as well as to assess the role played by these two regions in shaping memory and learning abilities.

Animals

Male C57BL/6 adult mice (n = 36; 2-5-month-old; 20-35 g) were used (RRID:MGI:5,656,552; Charles River, US). Animals were maintained on a 12 h light/dark cycle with ad libitum access to food and water. The temperature was controlled at 21 ± 1 ºC, and humidity was maintained at 50 ± 7%. Prior to surgery, mice were housed together (up to 5 per cage), but after surgery, they were individually housed to ensure their well-being. All experimental procedures were conducted at consistent time intervals to minimize potential circadian rhythm influences. Mice were regularly handled to reduce stress during experimental procedures.

All experimental procedures were reviewed and approved by the Ethical Committee for Use of Laboratory Animals of the University of Castilla-La Mancha (PR 2022-11-04 and PR-2018-05-11) and conducted in accordance with European Union guidelines (2010/63/EU) and Spanish regulations governing the use of laboratory animals in chronic experiments (RD 53/2013 on the care of experimental animals: BOE 08/02/2013).

Surgical procedure to generate an early amyloidosis model

Mice underwent surgery to enable chronic recording and drug injection (Figure 1A). The surgical procedure followed the methodology previously described [24, 27]. Initially, mice were anesthetized using a calibrated R580S vaporizer (RWD Life Science, US) with a flow rate: 0.5 L/min O₂. Anesthesia induction employed 4% isoflurane (#13400264, ISOFLO, Proyma S.L., Spain), which was then maintained at 1.5% isoflurane throughout the surgery. Following surgery, mice received intramuscular buprenorphine (0.01mg/kg; #062009, BUPRENODALE, Albet, Spain) for pain management and a topical healing cream (Blastoestimulina; Almirall, Spain).

For intracerebroventricular (icv.) administration of Aβ, animals underwent the implantation of a stainless steel, 26-G guide cannula (Plastics One, US) into the right ventricle (1 mm lateral and 0.5 mm posterior to bregma; depth from brain surface, 1.8 mm) [28]. The final positioning of the cannula was confirmed using Nissl staining (Figure 1A).

For chronic recording, bipolar electrodes, constructed from 50 μm Teflon-coated tungsten wire (Advent Research Materials, UK), were surgically implanted in each animal (Figure 1A). Two separate cohorts of animals were utilized, each with electrodes targeting distinct locations. In the first cohort, a subdural recording electrode was directed towards the surface of dorsomedial posterior parietal cortex (1.2 mm lateral and 1.8 mm posterior to bregma). In the second cohort, the recording electrode was aimed at the stratum radiatum beneath the CA1 area (1.2 mm lateral and 2.2 mm posterior to bregma; depth from brain surface, 1.0–1.5 mm) [28]. In all cases, a 0.1 mm silver wire was securely attached to the skull as ground, and both electrodes and grounding were then affixed to a 4-pin socket (Mouser Electronics, US), which was further attached to the skull using dental cement.

Following the surgical procedures, mice were allowed a recovery period of at least one week before any experimental interventions. Subsequently, animals were randomly assigned to either the Aβ_1-42 experimental group or the control group receiving vehicle (Phosphate-buffered saline, PBS). Aβ_1-42oligomers (oAβ_1-42) were prepared in PBS as described elsewhere [27, 29, 30] and procured from Abcam (#ab120301, Cambridge, UK). To administer oAβ_1-42, alert mice received a 3 µL icv. injection of the drug at a concentration of 1 μg/µL. The injection was performed through an insertion cannula within the implanted guide cannula using a Hamilton syringe, at a rate of 0.5 μL/min. Verification of the correct administration of oAβ_1-42 was confirmed through immunohistochemistry staining using a mouse anti-Aβ_1-42 antibody (#803001; dilution 1:500; Biolengend, US) as shown in Figure 1A.

In vivo electrophysiological recordings and analysis

Local field potential (LFP) activity was recorded using Dagan Corporation EX4-400 Quad Differential amplifiers (Dagan Corporation, Minneapolis MN United States) at a bandwidth of 0.1 Hz–10 kHz, through a high-impedance probe (2 × 1,012 Ω, 10 pF) in alert behaving mice placed in a plywood box (35 cm × 25 cm × 20 cm) and in the absence of any electrical stimulation. These recordings were digitally stored on a computer via an 8-channel analog-to-digital converter (CED 1401-plus; CED, Cambridge, UK).

In the first cohort of animals, LFPs were recorded from the PPC for 5 min before the icv. injections (pre-treatment values) and at 1-, 3- and 12-days post-injection (Figure 1B). These time points were selected for their relevance in the Barnes maze paradigm: at the biggening and end of the training phase (days 1 and 3, respectively) and during the test phase (day 12).

To analyze the LFP recordings, computer programs (Spike2 and SIGAVG; CED, Cambridge, UK) were used to display the LFP data in the time domain and export it in ASCII format. LFP epochs lasting 10 s (for power spectra) and 300 s (for time-frequency spectrograms) were selected for analysis, covering the four experimental conditions (days: PRE, D-1, D-3, D-12) and both groups of mice (oAβ_1-42and Vehicle). The LFP recordings were sampled at 5 kHz, and spectral analyses were conducted in the following frequency bands: delta (δ; 0-4 Hz), theta (Ɵ; 4-12 Hz), beta (β;12-30 Hz), low gamma (low γ; 30-48 Hz), and high gamma (high γ; 52-150 Hz).

The processing of LFP recordings involved frequency domain analysis using fast Fourier transforms (FFT) and time-frequency domain analysis using multi-tapered Fourier transforms (mTFT). These analyses were performed using custom program codes written in MATLAB (version 9.12, R2022a. The MathWorks, Natick, MA, USA) by one of the authors (R.S.-C.). Customized scripts from Chronux (versions 2.11/R2014 and 2.12/R2018 available at http://chronux.org/; [31]) were also employed for systematic spectral analysis [32, 33]. Probability maps for comparing pairs of spectrograms were generated as described in previous studies [33, 34]. Histograms of probability density for selected frequency bands were obtained based on Jackknifed estimation of variance between pairs of spectrograms (time-frequency plots of the LFP powers), covering all frequency values (resolution, df = 0.5 Hz) within each time window (resolution, dt = 0.5 s).

In a second cohort of animals, LFPs were recorded from the hippocampal CA1 area for 10 min before (pre-treatment values) and 1-h and 1-day post-icv. treatment (Figure 1C). Up to 5 min of artifact-free recordings were selected for subsequent spectral analysis using Spike2 software. Fourier transform (FT) was used to transform the signal into frequency-dependent functions. All LFPs data obtained were normalized using values from the pre-treatment day as 100%.

Barnes maze task

The Barnes maze (LE851BSW, Panlab, Spain) was employed to assess short- and long-term spatial memory in the first cohort of animals (Figure 1B), as previously described [27].

In brief, each trial commenced with the mouse positioned at the center of a maze measuring 92 cm in diameter and situated at 1 meter above the floor. The maze featured 20 escape holes, each measuring 5 cm in diameter, distributed along its periphery. Spatial cues, consisting of circles and squares of distinct colors, were positioned around the room. To prevent odor cues from influencing the trials, the maze was cleaned with 70% ethanol between each session.

The day prior to icv. injection, a habituation phase was conducted, allowing the mice to explore the maze for 90 s. Subsequently, three training days were implemented, commencing on the day following icv. treatment, with each day consisting of three trials separated by 15-min intervals. During each trial, the mice had 3 min to explore the maze or until they located the escape hole (measured by latency), which contained a box measuring 17.5 x 7.5 x 8 cm. Finally, on day 12 post-treatment, a single 90-s trial was conducted as a memory test. In this session, no escape holes were available, and the latency to reach the target hole was recorded. All sessions were recorded and analyzed using the Barnes-Smart video tracking software (Panlab, Spain).

Open field habituation task

The Open field (OF) habituation task was employed to evaluate a non-associative hippocampal-dependent learning process, specifically the exploratory habituation to a novel environment [35], in the second cohort of animals (Figure 1C).

Briefly, 1 h after the icv. injection, a training session (OF1) was conducted. During this session, mice were placed in the center of a square acrylic box (measuring 38 x 22.5 x 4 cm at the plexiglas base arena and 43.5 x 27.5 x 22.5 cm at the top) and allowed to freely explore the environment for a duration of 15 min. On the following day, a retention phase (OF2) was carried out, where the animals were reintroduced to the same environment for an equal amount of time.

To measure the change in exploratory behavior between these sessions, a LABORAS® apparatus (Laboratory Animal Behavior Observation Registration and Analysis System; Metris, Netherlands) was utilized. This system transforms the mechanical vibrations produced by the animals’ movements into electrical signals through a sensing platform located beneath the cage. Additionally, the distance traveled served as an indicator of motor activity, while the time spent in the periphery of the box (a perimeter of 5.4 cm from the walls) was used to assess anxiety-like behavior.

Spontaneous behaviors

To evaluate the overall health state of the animals, the LABORAS® was also utilized for stereotyped and locomotion behavioral testing (Figure 1B). 1 h after the icv. injection, mice were placed in a rectangular LABORAS® cage (measuring 23.5 x 17.5 x 4 cm at the plexiglas base arena and 26.5 x 21 x 10 cm at the top) for a single 15 min trial, as previously described [36].

Motor activity was quantified through measurements of locomotion, climbing, and rearing, while grooming behavior was used as an indicator of stress. All data were digitized and analyzed using the LABORAS® software (Metris, Netherlands).

Rotarod performance test

To assess the impact of the treatment on coordination and motor function, the rotarod apparatus (LE 8500, Panlab, Spain) was employed (Figure 1B). The day before treatment administration, mice were introduced to a 3 cm diameter black striated rod positioned 20 cm above the floor, which rotated at a constant low-speed of 6 rpm for 1 min, as a habituation exercise. Subsequently, 1 h post-icv. injection, mice’s time to fall off the rod was recorded in 6 consecutive trials, with the rod accelerating from 4 to 40 rpm over a 2-min period in each trial. Data were digitized and analyzed using the Sedacom software (Panlab, Spain).

Elevated plus maze

To evaluate anxiety-like behaviors [37], the elevated plus maze (LE 842, Panlab, Spain) was utilized (Figure 1B). 1 h after icv. injection, mice were placed in the center, facing one of the open arms of a cross-shaped methacrylate platform with two open arms (65 x 6 cm; without walls) and two enclosed arms (65 x 6 cm; 15-cm-high opaque walls) raised 40 cm above the floor. During a single 5-min session, the number of entries into the open arms and the time spent there were calculated to measure anxiety-like behavior. Additionally, the number of entries into the closed arms and the total entries (open + closed arms) were recorded as measures of locomotor activity [38]. All data were digitized and analyzed using the SMART 3.0 software (Panlab, Spain).

Tail suspension test

To assess depression-like behaviors, the tail suspension test was performed (Figure 1B) [39]. 1 h post-icv. injection, animals were suspended by their tails 19 cm above the ground in the tail suspension apparatus (BIO-TST5, Bioseb, US), within a PVC chamber (50 x 15 x 30 cm), for 6 min. Immobility time was recorded by the strain sensor as a measure of depression-like behavior, along with assessments of energy and power of movement to evaluate motor function. All data were digitized and analyzed using the BIO-TST 4.0 software (Bioseb, US).

Ex vivo field EPSP (fEPSP) recordings

1 (short-term) or 12 days (long-term) after icv. injections, coronal hippocampal slices were prepared as previously described [36] to explore CA3-CA1 synapse plasticity. After deep anesthesia with halothane (Fluothane, AstraZeneca, UK) and decapitation, brain was quickly removed and submerged in oxygenated (95% O2 – 5% CO2) ice-cold artificial cerebrospinal fluid (aCSF) containing (in mmol/L; all from Sigma, US): 118 NaCl (#S9888), 3 KCl (#P3911), 1.5 CaCl₂ (#499609), 1 MgCl₂ (#208337), 25 NaHCO₃ (#S6014), 30 glucose (#G8270), and 1 NaH₂PO₄(#S8282). The brain was placed on the stage of a vibratome (7000smz-2; Campden Instruments, UK) for the preparation of coronal slices (350 µm thick) containing the dorsal hippocampus. Subsequently, these slices were incubated for at least 1 h at room temperature (22°C) in aCSF.

For electrophysiological recordings, a single slice was transferred to an interface recording chamber (Warner instruments, US) that was continually perfused with oxygenated aCSF at a flow rate of 1 mL/min, using a peristaltic pump (Minipuls 3 Peristaltic Pump; Gilson, US). After a stabilization period of at least 10 min within the recording chamber, a borosilicate glass micropipette (1-3 MΩ; World precision instruments, US) connected to an extracellular recording amplifier (Neurolog system, Digitimer, US) was positioned in the stratum radiatum of CA1. Simultaneously, a tungsten concentric bipolar stimulating electrode (World precision instruments, US), connected to a Master‑9 stimulator (AMPI, Israel), was targeted at the Schaffer collateral pathway. Using a stimulus isolation unit (ISO/Flex; AMPI, Israel), biphasic, 60-µs-long, square-wave pulses were employed as stimuli, adjusted to ≈ 35% of the intensity necessary to evoke the largest field excitatory postsynaptic potential (fEPSP) response.

The baseline was established by collecting fEPSPs 10 min. LTP was then induced using a high-frequency stimulation (HFS) protocol, which consisted of five 1-s-long 100-Hz trains delivered at 30-s intertrain intervals. After HFS, fEPSPs were recorded for 60 min to evaluate the induction of LTP [36]. To align the effects of oAβ_1-42 on long term potentiation with the effects observed in the behavioral tasks, electrophysiology was conducted at 1 (short-term) and 12 days (long-term) post-icv. injection (Figure 1C).

The data were displayed using an oscilloscope (MDO3000; Tektronix, US) and digitized using the Spike 2 software (Cambridge electronic design, UK). Since synaptic responses were not affected by population spikes, the amplitude (i.e., the peak-to-peak value in mV during the rise-time period) of successively evoked fEPSPs was analyzed using the Signal software (Cambridge electronic design, UK).

Statistical analysis

The data were expressed as mean ± SEM and subjected to statistical analysis using one-way or two-way ANOVA. Time and treatment served as within- and between-subjects factors, respectively, and Tukey’s post hoc analysis was employed for further comparisons. In cases where data did not follow a normal distribution, the Mann-Whitney U test was utilized. When comparing only two groups, Student t-test was applied.

Statistical significance was defined at p < 0.05. All analyses were carried out using SPSS software v.24 (RRID:SCR_002865; IBM, US) and GraphPad Prism software v.8.3.1 (RRID:SCR_002798; Dotmatics, US). The final figures were generated using CorelDraw X8 Software (RRID:SCR_014235; Corel Corporation, Canada).

3.1. Disruption of cortical oscillatory activity by oA β ₁₋₄₂ 3 days after icv. administration

The coordinated activity between the PPC and the hippocampus plays a pivotal role in supporting memory processes, especially spatial memory [40]. As the initial step in our study, to assess the impact of oAβ₁₋₄₂ icv. administration on spatial memory, we conducted a Barnes maze task—a specialized evaluation of this form of memory [41]. This evaluation was carried out with a first cohort of animals (n = 11 per group) (Fig. 2A). The animals underwent training (days 1 and 3) and testing (day 12) in the Barnes Maze to evaluate both short-term and long-term spatial memory, as described previously [27]. A two-way ANOVA unveiled a significant treatment effect (Fig. 2B; F_(1,20) = 10.85, p = 0.0036), as the oAβ₁₋₄₂ group displayed an elevated latency to locate the escape hole on all tested days (p < 0.05 in all cases). This suggests that a single icv. injection of oAβ₁₋₄₂ disrupts spatial memory as early as 1 day post-injection and extends this disruption, at least, up to 12 days post-injection, affecting both short-term and long-term memory.

Then, to elucidate the relationship and implications of the PPC neuronal activity in spatial memory and to understand the impact of oAβ₁₋₄₂ icv. administration on this region, we conducted measurements of cortical oscillatory activity (Fig. 2D) using the same cohort of animals across the same time points (pre-treatment, and days 1, 3 and 12 post-treatment). We performed a systematic spectral analysis employing FFT in the frequency domain on LFP recordings (n = 6 mice per group, NE = 180 epochs per group, of 10 s each).

In Fig. 2C, the averaged power spectra (n = 180 individual spectra per treatment) of the raw LFP activity recorded during these four days is depicted, with the fundamental harmonic centered at 8 Hz in the theta frequency band (4–12 Hz) for both groups and on all days. Subsequently, a more comprehensive statistical analysis of the following frequency bands was conducted: δ (1–4 Hz), Ɵ (4–12 Hz), β (12–30 Hz), low γ (30–48 Hz) and high γ (52–150 Hz), represented as a percentage of the pre-treatment session (Fig. 2E-I).

The data revealed that in the vehicle group, delta (Fig. 2E) and theta (Fig. 2F) frequencies progressively decreased during the learning process (days 1 and 3 posttreatment) and almost returned to baseline (pre-treatment) levels on the test day (day 12 posttreatment). However, the oAβ₁₋₄₂-treated mice exhibited this decline in spectral power only on the first day of the learning process, after which both frequencies increased (days 3 and 12 post-treatment). As a result, both delta (F_(1,1432) = 26.52, p < 0.0001) and theta (F_(1,1432) = 56.11, p < 0.0001) exhibited significant treatment effects when compared to the control, with post hoc analysis indicating that the differences were specifically observed on days 3 and 12 after icv. injection.

Regarding beta (Fig. 2G) and low (Fig. 2H) and high (Fig. 2I) gamma frequencies, these remained stable in the vehicle group throughout the days analyzed. Conversely, akin to the observed patterns in slow-wave rhythms (delta and theta), the oAβ₁₋₄₂ group demonstrated a significant enhancement of these oscillations on days 3 and 12 posttreatment. Consequently, a significant treatment effect was observed in beta (F_(1,1432) = 31.80, p < 0.0001) and both low (F_(1,1432) = 35.22, p < 0.0001) and high (F_(1,1432) = 45.12, p < 0.0001) gamma frequencies, with the post hoc analysis revealing that the differences were specifically observed on days 3 and 12 posttreatment.

Furthermore, the dynamic evolution of LFP spectral powers was assessed in the vehicle and oAβ₁₋₄₂-treated groups (Fig. 3) throughout the selected days before (PRE) and after (D-1, D-3, D-12) the treatment (Fig. 3B-C). Time-frequency spectrograms of the LFPs were obtained through 18 tapered Fourier transforms, with each corresponding to the average of 6 epochs × 3 tapers. These transformations had a frequency width of 1 Hz and a moving time-window of 2 s, shifted in dt = 500 ms increments. The results collected allowed to confirm that the maximum spectral power consistently appeared in the theta band (4–12 Hz, centered at 8 Hz) across all cases. However, there were varying degrees of contribution to the theta fundamental rhythm. In Fig. 3, panels A and D depict probability density histograms resulting of the multiple comparisons between pairs of spectrograms. Black bars (indicating type + 1 inference; E2nd (estimation of power in second) ≫ E1st (estimation of power in first)) and gray bars (indicating type − 1 inference; E2nd ≪ E1st) denote significant statistical differences (p < 0.05; Jackknifed estimates of the variance) in mean spectral powers. White bars (indicating type 0 inference; E2nd ≈ E1st) signify no significant differences (p > 0.05). Histograms on the left in Fig. 3A and D reveal that spectral powers of LFPs recorded in PPC during the first day after the injection were lower than those obtained before the injection [vehicle (D-1 vs. PRE: types + 1 and 0 inferences were predominant (F_{(2, 1788)} = 1.47 × 10³, p < 0.001)); oAβ₁₋₄₂ [D-1 vs. PRE: type + 1 inferences were predominant (F_{(2, 1788)} = 1.42 × 10³, p < 0.001))] for the theta frequency band. Significant differences were observed when comparing spectral powers between the three selected days following injection, both in the oAβ₁₋₄₂ (D-1 vs. D-3: type + 1 inferences were predominant (F_{(2, 1788)} = 2.99 × 10³, p < 0.001); D-1 vs. D-12: type + 1 inferences were predominant (F_{(2, 1788)} = 1.49 × 10³, p < 0.001)) and the vehicle groups (D-1 vs. D-3: type 0 inferences were predominant (F_{(2, 1788)} = 0.94 × 10³, p < 0.001); D-1 vs. D-12: type 0 inferences were predominant (F_{(2, 1788)} = 1.16 × 10³, p < 0.001)).

To summarize, for both experimental groups, the spectral powers corresponding to theta rhythm significantly decreased on the first day after injection (D-1 compared to the PRE day). However, in oAβ₁₋₄₂-treated mice there was a noticeable increase in theta-band spectral powers on the third day (D-3) after injection, in contrast to what was observed for LFPs from the PPC of vehicle mice whose spectral powers decreased. Finally, by the time day D-12 (post-injection) was reached, the power values were quite close to those on the PRE-injection day.

Surprisingly, spatial memory deficits were detectable from the first day post-treatment (D-1), even though the oscillatory activity of the PPC was not affected until the third day post-injection (D-3). These data suggest a potential impairment in hippocampal functionality induced by early amyloidosis, as previously demonstrated by our group and others [27, 42], at an earlier stage than the alteration of the PPC’s network activity.

3.2. Alterations in hippocampal memory, oscillations, and synaptic plasticity induced by oA β ₁₋₄₂ icv. injection within 24 h

To further investigate the early impact of amyloidosis on hippocampal functionality, we conducted experiments with a second cohort of animals, aiming to assess the effects of oAβ₁₋₄₂ icv. administration on hippocampal-dependent memory, hippocampal oscillatory activity, and long-term synaptic plasticity (Fig. 4).

In this instance, we chose to evaluate habituation memory to a novel environment, a type of memory closely related to hippocampal function [35]. To achieve this, we utilized an open field habituation test, which also enables the assessment of shorter time periods, facilitating the exploration of hippocampal functionality in the early stages of amyloidosis-induced alterations. 1 h after treatment, animals (n = 7 mice per group) were placed in an open field (OF1, training session) for 15 min. During this session, the exploratory activity of both groups progressively reduced (Fig. 4A; Vehicle: F_(14,84) = 5.9, p < 0.001; oAβ₁₋₄₂: F_(14,84) = 15.52, p < 0.001), indicating proper encoding of habituation memory. 24 h after icv. treatment, animals were reintroduced into the open field arena (OF2, recall session). Here, a significant decrease in exploratory activity was observed in the control group (Fig. 4B; t₍₆₎ = 2.77, p = 0.032), indicating their ability to remember the arena. In contrast, this habituation effect was not observed in oAβ₁₋₄₂-treated mice (Fig. 4B; t₍₆₎ = 0.17, p = 0.873), suggesting a deterioration in memory recall for this group. Furthermore, during this recall session (OF2), a significant treatment effect was found, with oAβ₁₋₄₂-treated mice covering a longer distance than vehicle mice (Fig. 4B; t₍₁₂₎ = 2.19, p = 0.049). As all animals, regardless treatment, decreased exploration along the training session (Fig. 4B, left graph), but only oAβ₁₋₄₂-treated mice showed impaired retrieval during recall testing (Fig. 4B, right bar graph), it could be hypothesized that, in addition to retrieval, storage and or consolidation processes, more likely than encoding, could also be impaired by oAβ₁₋₄₂. In summary, these data suggest that early amyloidosis clearly impairs exploratory habituation memory retrieval, and these alterations occur within the first 24 h post-injection.

Having established the impact of amyloidosis on hippocampal-dependent memory, our next objective was to investigate the role of hippocampal neuronal activity in these alterations. Thus, we analyzed the oscillatory activity of the CA1 hippocampal region at different time points during the open field habituation task (pre-icv. injections and 1 and 24 h posttreatment). To achieve this, recording electrodes were implanted in the CA1 area of the mice’s brains (Fig. 4C, n = 8 mice per group), and the same frequency bands as previously analyzed in the PPC were examined, represented as a percentage of the pre-treatment session. Results revealed that in mice treated with oAβ₁₋₄₂, a decrease in the spectral power was observed in all analyzed rhythms starting from 1-h post-injection and persisting, at least, up to 24 h post-injection, compared to the control animals (Fig. 4D-H). This decrease due to treatment was statistically significant in both theta (Fig. 4E; F_{(1, 42)} = 14,41, p = 0.0005) and low gamma (Fig. 4G; F_{(1, 42)} = 7,897, p = 0.0075) rhythms. This suggests that icv. injection of oAβ₁₋₄₂ can lead to alterations in hippocampal oscillatory activity as early as 1 h post-injection, well before the observed effects in the PPC.

Finally, since hippocampal-dependent memory relies not only on oscillatory activity but also on synaptic plasticity [43], this second cohort of animals was used to evaluate hippocampal LTP ex vivo. To match the potential effects with those observed in the in vivo recordings and behavioral tasks, ex vivo electrophysiology was carried out 1 (short-term; n = 6 slices vehicle, 7 slices oAβ₁₋₄₂; Fig. 4I-J) and 12 days (long-term; n = 8 slices vehicle, 8 slices oAβ₁₋₄₂; Fig. 4I and K) post-icv. injection. In both time points, while in slices from vehicle-treated mice the HFS protocol resulted in approximately 130% potentiation of the response evoked in CA1, in slices from mice treated with oAβ₁₋₄₂, the induction of LTP was hindered, leading to a depression of the fEPSP (approximately 80% of the baseline) in response to the same HFS protocol (short-term: F_(1,11) = 28.96, p = 0.0002; Long-term: F_(1,14) = 45.56, p < 0.0001).

These results indicate the hippocampus’s special vulnerability to oAβ₁₋₄₂ icv. administration, as physiological hippocampal deficits manifest as early as 1 h post-treatment, preceding the observed effects in the PPC. The subsequent reflection of alterations in the hippocampal synaptic network in the PPC confirm the intricate connectivity between these two regions. This emphasizes the importance of their proper functioning for optimal cognitive performance. Altogether, these findings enhance our understanding of the temporal progression of Aβ peptide’s deleterious effects in the early stages of amyloidosis.

3.3. Lack of effects of oA β ₁₋₄₂ icv. injection on locomotion, energetic state and emotional well-being

To ensure that the observed alterations following oAβ₁₋₄₂ injection were indeed related to specific impairments in the PPC and the hippocampus rather than general health issues, a battery of behavioral tests was conducted to evaluate various behavioral aspects.

Stereotyped behaviors were assessed and LABORAS® data revealed that all experimental groups spent equivalent amounts of time engaged in the various behaviors analyzed (Fig. 5A): locomotion (U = 47, p = 0.821), climbing (U = 46, p = 0.691), rearing (U = 39, p = 0.374) and grooming (U = 40.5, p = 0.471). Using an OF, no disparities were observed in the distance traveled (Fig. 5B; t₍₁₈₎ = 0.28, p = 0.785), a measure of motor activity, nor in the time spent in the periphery (Fig. 5B; t₍₁₈₎ = 0.266, p = 0.793), indicating that the animals did not exhibit anxiety-like behaviors. Locomotion was further assessed through the number of entries into closed (t₍₁₇₎ = 0.14, p = 0.887) and total arms (t₍₁₇₎ = 0.21, p = 0.834) in the elevated plus maze and, once again, with no differences found between groups (Fig. 5C). Moreover, all animals displayed similar numbers of entries (U = 37, p = 0.49) and time spent in open arms (U = 40, p = 0.671) in the elevated plus maze (Fig. 5C), reinforcing that induced amyloidosis did not elevate anxiety-like behaviors. All groups equally improved their performance in the rotarod across trials (Fig. 5D; Vehicle: F_(5,45) = 3.388, p = 0.011; oAβ_1− 42: F_(5,35) = 3.926, p = 0.006) and there were no differences in the latency to fall off the rod during the entire session (Fig. 5D; F_(1,16) = 0.005, p = 0.943), indicating no disparities in motor coordination due to treatment. Finally, all animals exhibited the same levels of energy (t₍₁₈₎ = 0.829, p = 0.418) and power of movement (t₍₁₈₎ = 0.216, p = 0.831), along with identical immobility times (t₍₁₈₎ = 0.954, p = 0.353) in the tail suspension test (Fig. 5E). This suggests that oAβ_1− 42 did not induce muscle weakness or increase depression-like behaviors.

In summary, these results confirm that the overall health state, locomotor function and emotional state remained consistent across both treated groups. Therefore, the impairments observed can be attributed to a specific disruption in the PPC-hippocampal circuitry caused by oAβ₁₋₄₂.

In the early stages of AD, imbalances in neuronal activity within various brain circuits, including the cortex and hippocampus, have been consistently observed in both patients and murine models [44, 45]. Evidence supports the role of soluble oAβ in contributing to the cognitive deficits commonly associated with these altered neuronal states seen during the preclinical stages of the disease [46]. Previous research from our group has delved into the impact of hippocampal amyloidosis induced by oligomeric forms of Aβ₁₋₄₂, revealing increased excitability that coincides with disrupted LTP, irregular patterns in hippocampal oscillatory activity, and deficits in hippocampal-dependent memory that persists over time [24, 27, 47, 48].

To gain a deeper understanding of how Aβ influences cognitive processes, particularly hippocampal-dependent memory, it becomes crucial to consider other regions with which the hippocampus establishes connections and understand how Aβ deleterious action progresses. Thus, this study has placed particular emphasis on investigating the time sequence between the hippocampus and the PPC impairments, as these regions are known to synchronize their neuronal activity to support functions such as spatial memory formation or episodic memory retrieval [40, 49]. To initiate our exploration, we conducted a Barnes maze test to assess spatial memory. Our findings revealed a significant increase in the latency to find the target hole 24 h after icv. administration of oAβ₁₋₄₂ peptide. This disruption in spatial navigation memory persisted for at least 12 days after amyloidosis induction. These results have dual implications. Firstly, they suggest that oligomeric forms of Aβ may be affecting the functionality of the PPC and the hippocampus, both crucial for spatial memory [40, 50]. This is consistent with our previous research, which demonstrated that acute amyloidosis induced by a single injection of oAβ₁₋₄₂ impairs long-term spatial memory [27]. Furthermore, it aligns with reports indicating a compromised spatial navigation in early phases of the disease [51, 52]. Secondly, these findings confirm the suitability of our amyloidosis model to mimic the early stages of AD, previously validated in both male and female mice without finding differences between the two [27]. This allowed us to use only males in this study to maintain a greater sample homogeneity and to work in accordance with the 3R’s principle of minimizing the number of animals used, with the confidence that we would have observed similar results in females.

Subsequently, to explore the role of PPC functionality in this process, we surgically implanted subdural electrodes in the PPC to record LFPs in alert mice, enabling us to examine the effect of oAβ₁₋₄₂ icv. administration on cortical oscillatory activity. Oscillatory activity of neural networks arises from the activity of different neuronal populations, and their synchronization defines the amplitude (or spectral power) of oscillations at different frequency intervals. In this context, GABAergic inhibitory interneurons play a pivotal role in coordinating the activity and synchronization of excitatory neurons and other interneurons, thereby generating oscillations across different frequency bands [19]. In LFP recordings, dysfunction within neuronal networks manifests as alterations of oscillatory activity across different frequency intervals associated with cognitive processes [19, 53]. Our LFP recordings revealed that, while oscillatory activity in the PPC remained unaltered 24 h after oAβ₁₋₄₂ icv. injection, a significative increase in spectral power across all analyzed rhythms emerged at 3 days post-icv. injection, persisting for at least 12 days post-icv. injection. This change was particularly pronounced within the theta rhythm, where the heightened spectral power enabled us to conduct a more comprehensive temporal analysis. This analysis unveiled an aberrant increase in spectral power within the theta band, starting from the third day post-injection in amyloidosis-affected animals. Consistent with our observations, alterations in theta and gamma rhythms have been documented in electroencephalogram (EEG) recordings of AD patients [54, 55] and in LFP recordings of murine models of the disease [56, 57]. Furthermore, both oscillations interact to create the theta-gamma neural code, involved in sensory processing, memory, and learning [58]. The accurate encoding of memories is associated with an increase in gamma activity accompanied by a decrease in low-frequency oscillations, including theta, in neural networks relevant to the task at hand [19]. Along these lines, variations in the spectral power of theta or gamma rhythms induced by oAβ₁₋₄₂ suggest a possible disruption of theta-gamma interactions, as also described in early stages of AD in non-transgenic [24] and transgenic murine models of the disease [59]. Additionally, EEG recordings from patients in the preclinical stages of AD have also revealed alterations in other cortical rhythms, including delta and beta rhythms, which may contribute to an increased risk of future cognitive decline [60]. Furthermore, these findings align with other studies that describes how neuronal hyperactivity induced by Aβ in the early stages of AD and in murine models of amyloidosis can contribute to the dysfunction of neural networks and trigger epileptiform activity [22, 61].

Furthermore, a noteworthy observation that merits further explanation is the temporal dissociation between the emergence of spatial memory deficits (which were evident from the same day post-treatment) and the absence of alterations in PPC oscillatory activity until 3 days post-injection. Neuronal activity within a specific region is significantly influenced by afferent signals it receives from other interconnected brain regions [62]. Thus, the LFPs obtained from the surface of the PPC could reflect changes in other structurally and functionally interconnected areas, including the hippocampus. In this scenario, the icv. administration of the oAβ₁₋₄₂ might trigger acute amyloidosis primarily at the hippocampal level, which would be affected initially. As a result, oAβ-induced alterations in hippocampal neuronal activity would interfere early with hippocampal-dependent memory, yet the effects might not manifest in cortical oscillatory activity until several days later, corresponding to the long-term consolidation of this memory type. To examine this hypothesis, we assessed a second cohort of animals with electrodes implanted in dorsal CA1 to analyze short-term changes in hippocampal-dependent memory and hippocampal oscillatory activity.

At the behavioral level, we examined how oAβ-induced hippocampal amyloidosis affects different aspects of hippocampal-dependent memory processing. To do so, we conducted an open field habituation test, a tool that allows us to assess two specific types of habituation processes: intrasession, which evaluates memory formation within the same session, and intersession, which assesses memory recall, across different sessions, both of which dependent largely on the hippocampus [63, 64]. In this test, both the control group and the mice receiving oAβ₁₋₄₂, displayed a gradual memory formation curve during the initial session, very likely indicating not impaired encoding of memory. However, they exhibited deficits in habituation memory retrieval 24 h after the injections. This results are consistent with previous studies describing impairments in habituation memory to a new context and object recognition memory in models of early amyloidosis [24, 27, 48, 65], and substantiate the results observed in the Barnes maze test, which also pointed to memory impairments. It is worth noting that the PPC, renowned for its role in memory retrieval [49], may be implicated in these observed memory deficits. Subsequently, to gain insights into hippocampal functionality and elucidate the underlying factors contributing to the observed hippocampal-dependent memory impairments, we conducted recordings of the oscillatory activity in the CA1 of the hippocampus. LFPs unveiled a significant reduction in theta and low gamma rhythms as early as 1 h following the administration of oAβ₁₋₄₂ suggesting that alterations in oscillatory activity occur in the hippocampus before the PPC, although recordings from both regions were not simultaneously obtained. Importantly, these changes coincided with the onset of spatial and habituation memory deficits, as indicated by the results from the Barnes maze and Open field habituation tests. Even though no statistically significant alterations were observed in the high gamma rhythm within the hippocampus, this observation could be attributed to the inherent characteristics of high gamma activity, including its low spectral power and broad frequency range, which make it less amenable to precise analyses. These findings are in line with previous research describing alterations in hippocampal oscillations induced by oAβ₁₋₄₂ [24], the biologically active isoform Aβ₂₅₋₃₅ [65], or in transgenic models [59]. Moreover, the early decline in theta and gamma rhythms within the hippocampus was followed by an increase in the spectral power of these rhythms within the PPC. This phenomenon may suggest the existence of a compensatory mechanism that, paradoxically, might contribute to an abnormal state. This raises intriguing questions regarding the potential role of the PPC in the long-term alterations we observed in our amyloidosis model.

Furthermore, it is important to recognize the intricate relationship between neural network activity and synaptic plasticity, with each mutually influencing the other [66]. Neuronal plasticity refers to the brain’s ability to adapt and remodel synapses, circuits, and neural networks in response to pathological conditions or processes that could potentially compromise their functionality or structural integrity. This adaptability leads to the generation of compensatory mechanisms, ultimately preventing the development of neuropathological disorders. Therefore, loss of synaptic plasticity may increase the vulnerability to network dysfunction or circuit loss, as neural circuits and networks become less capable of adapting to pathological alterations [19, 67]. This raises the question of whether, in our model, hippocampal synaptic plasticity is also compromised. To address this point, we obtained hippocampal slices from mice with early amyloidosis and induced an LTP at the CA3-CA1 synapse ex vivo. Here, we observed that while the HFS protocol induced LTP in vehicle-injected animals, it resulted in long-term depression (LTD) in oAβ₁₋₄₂-treated animals. This effect was persistent even 12 days after a single oAβ₁₋₄₂ injection. As discussed in our previous work, this modification of the induction threshold for LTP/LTD is likely attributed to the hyperexcitability induced by the peptide [27]. This is consistent with the proposal of the Bienenstock, Cooper, and Munro (BCM) theory, which suggests that a state of neuronal hyperactivity can raise the threshold for LTP induction, favoring LTD and preventing excessive neuronal activity [68, 69]. Given the established association between neuronal oscillations and LTP [66], it is plausible that the icv. administration of the oAβ₁₋₄₂ peptide exerts an influence on long-term plasticity processes through its impact on oscillatory activity, and vice versa, potentially impacting memory and learning abilities.

In conclusion, our findings offer valuable insights into the impact of early amyloidosis on neuronal connectivity and cognitive processes. Beyond the initial disruptions in hippocampal synaptic and neural network functioning, which underlie hippocampal-dependent memory deficits, we have uncovered atypical patterns in the oscillatory activity of the PPC, a region intricately connected with the hippocampus [5]. Significantly, these alterations manifest several days following hippocampal disturbances and may account for the enduring effects on spatial memory observed in our amyloidosis model. This underscores the importance of investigating interregional communication for a deeper comprehension of early amyloid pathology and suggests potential future research into therapeutic strategies aimed at addressing these initial neural network disruptions in AD. Moreover, given the suitability of EEG metrics as potential biomarkers for the preclinical stages of AD [60] and the association of PPC dysfunction with a higher risk of MCI to AD conversion [25], our findings point out the potential of PPC oscillatory activity as a valuable tool for the early detection and intervention in AD.

Aβ

amyloid-β

oAβ₁₋₄₂

oligomeric amyloid-β₁₋₄₂

aCSF

artificial cerebrospinal fluid

Alzheimer’s disease

BCM

Bienenstock, Cooper, and Munro

dPPC

dorsal posterior parietal cortex

E2nd

estimation of power in second

E1st

estimation of power in first

EEG

electroencephalogram

fEPSP

field excitatory postsynaptic potential

FFT

Fast Fourier transform

fMRI

functional magnetic resonance imaging

Fourier transform

HFS

high-frequency stimulation

icv.

intracerebroventricular

LABORAS®

Laboratory Animal Behavior Observation Registration and Analysis System

LFP

local field potential

LTD

long-term depression

LTP

long-term potentiation

MCI

mild cognitive impairment

mTFT

multi-tapered Fourier transform

open field

PBS

phosphate-buffered saline

PPC

posterior parietal cortex

vPPC

ventral posterior parietal cortex

Ethics approval

All experimental procedures were reviewed and approved by the Ethical Committee for Use of Laboratory Animals of the University of Castilla-La Mancha (PR‑2022-11-04 and PR-2018-05-11) and conducted according to the European Union guidelines (2010/63/EU) and the Spanish regulations for the use of laboratory animals in chronic experiments (RD 53/2013 on the care of experimental animals: BOE 08/02/2013).

Consent for publication

Not applicable.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

This work was supported by MCIN/AEI/10.13039/501100011033 (grant number PID2020-115823-GB100) and JCCM and ERDF A way of making Europe (grant number SBPLY/21/180501/000150) and 2022-GRIN-34354 grant by UCLM/ERDF intramural funds to JDNL and LJD; and ANDALUSIA ERDF (UPO-1380660) to RSC. AC held a Margarita Salas Postdoctoral Research Fellow funded by European Union NextGenerationEU/PRTR. GIL held a predoctoral fellowship granted by UCLM/ESF Plan Propio de Investigación Program.

Authors’ contributions

LJD and JDNL were responsible for the initial conceptualization; RJH, AC, GIL and DJ performed the experiments; RJH, AC, GIL, SD, VCA and RSC analyzed the data; SD and AC were responsible for writing the original draft; SD, AC, RSC, JDNL and LJD did the writing – review and editing. LJD and JDNL were responsible for funding acquisition. All authors read and approved the final manuscript.

Acknowledgements

Not applicable.

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Posterior parietal cortex oscillatory activity shapes persistent spatial memory impairments induced by soluble amyloid-β oligomers

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Background

Methods

Results

Discussion

Conclusions

Abbreviations

Declarations

Ethics approval

Consent for publication

Availability of data and materials

Competing interests

Funding

Authors’ contributions

Acknowledgements

References

Additional Declarations

Status:

Version 1