Effects of coffee on cognitive function.

This chapter thoroughly examines coffee's impact on cognitive function. It synthesizes research findings involving animals and humans, investigating coffee's influence on various memory and cognitive aspects, including short-term/working memory, long-term memory, attention, vigilance, executive functions, and processing speed. The chapter also discusses moderating factors, such as dose-response relationships, individual differences, age, and habitual consumption patterns, that influence the cognitive effects of coffee. Additionally, it addresses the potential risks and adverse effects associated with coffee intake, memory, and cognitive function, including stress and anxiety, sleep disturbances, cardiovascular effects, and addiction. Studies suggest moderate coffee intake improves attention, processing speed, decision-making, and certain executive functions. However, the effects vary depending on factors like dosage, individual traits, age, and sleep habits. Despite potential benefits, coffee consumption may lead to adverse effects such as anxiety, sleep issues, cardiovascular concerns, and dependency. Future research should address methodological concerns, incorporate neuroimaging methods, explore interactions with other substances, and investigate long-term effects and therapeutic uses. Understanding coffee's neuroscience can shed light on its role in daily life and health.

Coffee's protective mechanisms against neurodegeneration.

A widely consumed beverage, coffee has emerged as a potential protective natural agent against neurodegenerative diseases. This chapter explores the intricate mechanisms by which coffee and its bioactive compounds exert neuroprotective effects. The antioxidant properties of coffee polyphenols, such as chlorogenic acid and caffeic acid, mitigate oxidative stress and neuroinflammation. Coffee modulates neurotransmitter systems, including dopaminergic, cholinergic, and glutamatergic pathways implicated in neurodegeneration. Additionally, coffee activates neuroprotective signaling cascades, such as the Nrf2 pathway, and inhibits pro-inflammatory pathways like NF-κB. Coffee components also influence mitochondrial function, biogenesis, and energy metabolism, thereby promoting neuronal survival. Furthermore, coffee suppresses microglial activation and modulates microglial phenotypes, reducing neuroinflammatory responses. Epidemiological studies and clinical trials provide insights into the potential benefits of coffee consumption on cognitive function and neurodegenerative disease risk. However, future research should focus on identifying specific coffee bioactive compounds and their mechanism of action. This chapter highlights the multifaceted neuroprotective mechanisms of coffee, paving the way for future research and potential therapeutic interventions.

Coffee and mental disorders: How caffeine affects anxiety and depression.

Caffeine, the main psychoactive component in coffee, has garnered significant attention for its potential impact on the most prevalent mental health conditions like anxiety and depression. This chapter comprehensively examines the neurobiological effects of caffeine, its influence on anxiety and depression, and relevant clinical studies. Caffeine exerts its psychostimulant effects primarily through antagonizing adenosine receptors, modulating neurotransmitter systems, and influencing intracellular calcium signaling in the brain. Caffeine exhibits dose-dependent effects. While moderate caffeine consumption is safe in healthy adults and may offer benefits for mental health, excessive intake is linked to adverse effects on neurological and psychiatric health and can aggravate symptoms, highlighting the importance of adjusting consumption patterns. High caffeine intake correlates with elevated anxiety levels, especially in individuals predisposed to anxiety disorders. However, the relationship between caffeine consumption and the risk of depression is intricate, with some studies suggesting a potential protective effect of moderate intake, while others find no significant association. Individual variations in caffeine metabolism, sensitivity, and genetic factors considerably impact responses to caffeine. The chapter also explores the therapeutic potential of caffeine as an adjunct treatment and outlines challenges and future research directions in elucidating caffeine's multifaceted role in mental health.

Coffee and sleep: Benefits and risks.

Consuming coffee, a widely enjoyed beverage with caffeine, can impact the central nervous system and disturb sleep if taken too close to bedtime. Caffeine impacts sleep by slowing the onset, blocking adenosine receptors, lowering deep sleep levels, disrupting sleep patterns, and lessening rapid eye movement sleep. Although coffee can help with alertness in the morning, it may disturb sleep in the evening, particularly for individuals who are sensitive to caffeine. To enhance the quality of sleep, reduce the consumption of caffeine in the afternoon and evening, refrain from drinking caffeine before going to bed, and choose decaffeinated drinks instead. Variables such as personal reactions, ability to handle caffeine, and engagement with other compounds also influence the impact of coffee on sleep. Keeping track of how much caffeine you consume and your sleeping habits can assist in recognizing any disturbances and making needed changes. Furthermore, taking into account variables such as metabolism, age, and the timing of coffee consumption can assist in lessening the effects of coffee on sleep. In general, paying attention to the amount of caffeine consumed from different sources and consuming it at the right times can assist in preserving healthy sleep patterns even while enjoying coffee.

Mild exercise plus levothyroxine ameliorate deficits of spatial navigation, anxiety profile, and hippocampal BDNF in hypothyroid male offspring rats.

PURPOSE: Levothyroxine (LEV) monotherapy cannot completely improve cognitive and behavioral impairments induced by hypothyroidism, whereas a combination therapy of exercise and LEV may ameliorate these deficits. This study aimed to determine the effects of mild-intensity forced exercise and LEV treatment on the anxiety profile and cognitive functions in male offspring of hypothyroid dams. METHOD: Twenty-four female rats (mothers) were randomly divided into sham (healthy) and hypothyroidism groups and then placed with male rats to mate. The presence of vaginal plaque confirmed pregnancy (gestational day, GD 0). 6-propyl-2-thiouracil (PTU, 100 ppm) was added to the drinking water of the hypothyroidism group from GD 6 to the 21st postnatal day (PND). The sham group received tap water. On PND 21, serum T4 levels of mothers, and 10 pups were measured to confirm hypothyroidism. Sixty-four male pups were left undisturbed for 30 days and then were divided into eight groups that received saline or LEV (50 µg/kg, i.p.) with or without forced mild-intensity exercise. After 14 days of interventions, anxiety-like behaviors, spatial learning and memory, and hippocampal brain-derived neurotrophic factor (BDNF) levels were evaluated. FINDING: A pre and postnatal PTU-induced model of hypothyroidism increased anxiety-like behaviors, impaired spatial learning and memory, and decreased hippocampal BDNF levels in male offspring rats. LEV alone increased BDNF levels and improved spatial learning. Exercise alone increased BDNF levels, improved spatial learning and memory, and decreased anxiety-like behaviors. Exercise plus LEV more effectively improved anxiety-like behaviors and spatial learning than exercise or LEV alone. CONCLUSION: Practically, these pre-clinical findings highlight the importance of the combination of exercise and LEV regimen in treating patients with hyperthyroidism.

Involvement of relaxin-family peptide-3 receptor (RXFP3) in the ventral dentate gyrus of the hippocampus in spatial and fear memory in rats.

The neuropeptide relaxin-3 and its cognate receptor, relaxin family peptide-3 receptors (RXFP3), have been implicated in modulating learning and memory processes, but their specific roles remain unclear. This study utilized behavioral and molecular approaches to investigate the effects of putatively reversible blockade of RXFP3 in the ventral dentate gyrus (vDG) of the hippocampus on spatial and fear memory formation in rats. Male Wistar rats received bilateral vDG cannula implantation and injections of the RXFP3 antagonist, R3(BΔ23-27)R/I5 (400 ng/0.5 µL per side), or vehicle at specific time points before acquisition, consolidation, or retrieval phases of the Morris water maze and passive avoidance learning tasks. RXFP3 inhibition impaired acquisition in the passive avoidance task but not the spatial learning task. However, both memory consolidation and retrieval were disrupted in both tasks following RXFP3 antagonism. Ventral hippocampal levels of the consolidation-related kinase p70-S6 kinase (p70S6K) were reduced RXFP3 blockade. These findings highlight a key role for ventral hippocampal RXFP3 signaling in the acquisition, consolidation, and retrieval of spatial and emotional memories, extending previous work implicating this neuropeptide system in hippocampal memory processing.

Corticosterone injection into the basolateral amygdala before and after memory reactivation impairs the subsequent expression of fear memory in rats: An interaction of glucocorticoids and ß-adrenoceptors.

Glucocorticoid administration, before or after fear memory reactivation, impairs subsequent fear memory expression, but the underlying mechanisms are not well understood. The present study examined the role of basolateral amygdala (BLA) ß-adrenoceptors in the effects of intra-BLA corticosterone injection on fear memory in rats. Bilateral cannulae were implanted in the BLA of Wistar male rats. The rats were trained and tested using an inhibitory avoidance task (1 mA footshock for 3 s). Forty-eight hours after training, corticosterone (CORT, 5, 10, or 20 ng/0.5 µl/side) and the ß2-adrenoceptor agonist clenbuterol (CLEN, 10 or 20 ng/0.5 µl/side) or the ß-adrenoceptor antagonist propranolol (PROP, 250 or 500 ng/0.5 µl/side) were injected into the BLA before or right after memory reactivation (retrieval, Test 1). We performed subsequent tests 2 (Test 2), 5 (Test 3), 7 (Test 4), and 9 (Test 5) days after Test 1. The results demonstrated that CORT injection before Test 1 disrupted memory retrieval and reduced fear expression in Tests 2-5, possibly due to enhanced extinction or impaired reconsolidation. CORT injection after Test 1 also impaired reconsolidation and reduced fear expression in Tests 2-5. CLEN prevented, but PROP exacerbated, the effects of CORT on fear expression. The reminder shock did not recover fear memory in CORT-treated animals, suggesting that reconsolidation, not extinction, was affected. These results indicate that glucocorticoids and ß-adrenoceptors in the BLA jointly modulate fear memory reconsolidation and expression. Comprehending the neurobiology of stress and the impact of glucocorticoids on fear memory may lead to new treatments for stress and trauma-induced disorders such as PTSD.

Prangos ferulacea (L.) ameliorates behavioral alterations, hippocampal oxidative stress markers, and apoptotic deficits in a rat model of autism induced by valproic acid.

BACKGROUND: Prenatal exposure to valproic acid (VPA) may enhance the risk of autism spectrum disorder (ASD) in children. This study investigated the effect of Prangos ferulacea (L.) on behavioral alterations, hippocampal oxidative stress markers, and apoptotic deficits in a rat model of autism induced by valproic acid. METHODS: Pregnant rats received VPA (600 mg/kg, intraperitoneally [i.p.]) or saline on gestational day 12.5 (E 12.5). Starting from the 30th postnatal day (PND 30), the pups were i.p. administered Prangos ferulacea (PF, 100 and 200 mg/kg), or the vehicle, daily until PND 58. On PND 30 and 58, various behavioral tasks were used to evaluate pups, including the open field, elevated plus-maze, hot-plate, and rotarod test. On PND 65, the animals were euthanized, and their brains were removed for histopathological and biochemical assay. RESULTS: Prenatal exposure to VPA caused significant behavioral changes in the offspring, reversed by administering an extract of Prangos ferulacea (L.). Additionally, prenatal VPA administration resulted in increased levels of malondialdehyde and deficits in antioxidant enzyme activities in the hippocampus, including catalase and glutathione, ameliorated by PF. Likewise, postnatal treatment with PF improved VPA-induced dysregulation of Bax and Blc2 in the hippocampus and reduced neuronal death in CA1, CA3, and dentate gyrus. CONCLUSION: The findings of this study suggest that postnatal administration of PF can prevent VPA-induced ASD-like behaviors by exhibiting antiapoptotic and antioxidant properties. Therefore, PF may have the potential as an adjunct in the management of ASD.

Saffron and crocin ameliorate prenatal valproic acid-induced autistic-like behaviors and brain oxidative stress in the male offspring rats.

Autism is a neurobehavioral disease that induces cognitive and behavioral alterations, usually accompanied by oxidative stress in the brain. Crocus sativus (saffron) and its active ingredient, crocin, have potent antioxidative effects that may benefit autistic behaviors. This study aimed to determine the effects of saffron extract and crocin against brain oxidative stress and behavioral, motor, and cognitive deficits in an animal model of autism in male offspring rats. 14 female rats were randomly divided into the saline and valproic acid (VPA) groups. Then, they were placed with mature male rats to mate and produce offspring. VPA (500 mg/kg, i.p.) was injected on day 12.5 of pregnancy (gestational day, GD 12.5) to induce an experimental model of autism. 48 male pups were left undisturbed for 29 days. First-round behavioral tests (before treatments) were performed on 30-33 post-natal days (PND), followed by 28 days of treatment (PND 34-61) with saffron (30 mg/kg, IP), crocin (15 or 30 mg/kg, i.p.), or saline (2 ml/kg, i.p.). The second round of behavioral tests (after treatments) was performed on PND 62-65 to assess the effects of the treatments on behavioral and cognitive features. In the end, animals were sacrificed under deep anesthesia, and their brains were dissected to evaluate the brain oxidative stress parameters, including malondialdehyde (MDA), glutathione (GSH), and catalase (CAT). VPA injection into female rats increased anxiety-like behaviors, enhanced pain threshold, impaired motor functions, disturbed balance power, increased MDA, and decreased GSH and CAT in their male offspring. 28 days of treatment with saffron or crocin significantly ameliorated behavioral abnormalities, reduced MDA, and increased GSH and CAT levels. Brain oxidative stress has been implicated in the pathophysiology of autistic-like behaviors. Saffron and crocin ameliorate anxiety-like behaviors, pain responses, motor functions, and brain oxidative stress parameters in an experimental model of autism. Saffron and crocin may hold promise as herbal-based pharmacological treatments for individuals with autism. However, further histological evidence is needed to confirm their efficacy.

Hypothalamus and Post-Traumatic Stress Disorder: A Review.

Humans have lived in a dynamic environment fraught with potential dangers for thousands of years. While fear and stress were crucial for the survival of our ancestors, today, they are mostly considered harmful factors, threatening both our physical and mental health. Trauma is a highly stressful, often life-threatening event or a series of events, such as sexual assault, war, natural disasters, burns, and car accidents. Trauma can cause pathological metaplasticity, leading to long-lasting behavioral changes and impairing an individual's ability to cope with future challenges. If an individual is vulnerable, a tremendously traumatic event may result in post-traumatic stress disorder (PTSD). The hypothalamus is critical in initiating hormonal responses to stressful stimuli via the hypothalamic-pituitary-adrenal (HPA) axis. Linked to the prefrontal cortex and limbic structures, especially the amygdala and hippocampus, the hypothalamus acts as a central hub, integrating physiological aspects of the stress response. Consequently, the hypothalamic functions have been attributed to the pathophysiology of PTSD. However, apart from the well-known role of the HPA axis, the hypothalamus may also play different roles in the development of PTSD through other pathways, including the hypothalamic-pituitary-thyroid (HPT) and hypothalamic-pituitary-gonadal (HPG) axes, as well as by secreting growth hormone, prolactin, dopamine, and oxytocin. This review aims to summarize the current evidence regarding the neuroendocrine functions of the hypothalamus, which are correlated with the development of PTSD. A better understanding of the role of the hypothalamus in PTSD could help develop better treatments for this debilitating condition.

Systemic corticosterone administration impairs the late fear memory reconsolidation via basolateral amygdala glucocorticoid receptors: Dependence on the time window and memory age.

Glucocorticoid receptors (GRs) of the basolateral amygdala (BLA) play an important role in memory reconsolidation. The present study investigated the role of the BLA GRs in the late reconsolidation of fear memory using an inhibitory avoidance (IA) task in male Wistar rats. Stainless steel cannulae were implanted bilaterally into the BLA of the rats. After 7 days of recovery, the animals were trained in a one-trial IA task (1 mA, 3 s). In Experiment One, 48 h after the training session, the animals received 3 systemic doses of corticosterone (CORT; 1, 3, or 10 mg/kg, i.p.) followed by an intra-BLA microinjection of the vehicle (0.3 µl/side) at different time points (immediately, 12, or 24 h) after memory reactivation. Memory reactivation was performed by returning the animals to the light compartment while the sliding door was open. No shock was delivered during memory reactivation. CORT (10 mg/kg) injection 12 h after memory reactivation most effectively impaired the late memory reconsolidation (LMR). In the second part of Experiment One, immediately, 12, or 24 h after memory reactivation, GR antagonist RU38486 (RU; 1 ng/0.3 µl/side) was injected into BLA following a systemic injection of CORT (10 mg/kg) to examine whether it would block the CORT effect. RU inhibited the impairing effects of CORT on LMR. In Experiment Two, the animals received CORT (10 mg/kg) with time windows immediately, 3, 6, 12, and 24 h after memory reactivation. Again, CORT (10 mg/kg) injection 12 h after memory reactivation impaired LMR. Memory reactivation was performed in the third Experiment, 7, 14, 28, or 56 days after the training session. Injection of CORT (10 mg/kg) 12 h later had no significant effect on the LMR. The impairing effect of CORT was seen only in 2-day-old but not 7, 14, 28, and 56-day-old memories. GRs located in BLA seem to play an important role in the LMR of young memory, as with increasing the age of memories, they become less sensitive to manipulation.

Corticosterone injection into the dorsal and ventral hippocampus impairs fear memory reconsolidation in a time-dependent manner in rats.

Reconsolidation is an active process induced following the reactivation of previously consolidated memories. Recent studies suggest brain corticosteroid receptors may participate in the modulation of fear memory reconsolidation. Glucocorticoid receptors (GRs), with 10-fold lower affinity than mineralocorticoid receptors (MRs), are mainly occupied during the peak of the circadian rhythm, and after stress, so they probably have a more critical role than MRs in memory phases during stressful situations. This study investigated the role of dorsal and ventral hippocampal (DH and VH) GRs and MRs on fear memory reconsolidation in rats. Male Wistar rats with surgically implanted bilaterally cannulae at the DH and VH were trained and tested in an inhibitory avoidance task. The animals received bilateral microinjections of vehicle (0.3 µl/side), corticosterone (3 ng/0.3 µl/side), the GRs antagonist RU38486 (3 ng/0.3 µl/side), or the MRs antagonist spironolactone (3 ng/0.3 µl/side) immediately after memory reactivation. Moreover, drugs were injected into VH 90 min after memory reactivation. Memory tests were performed 2, 9, 11, and 13 days after memory reactivation. Results indicated that injection of corticosterone into the DH but not VH immediately after memory reactivation significantly impaired fear memory reconsolidation. Moreover, corticosterone injection into VH 90 min after memory reactivation impaired fear memory reconsolidation. RU38486, but not spironolactone reversed these effects. These findings indicate that corticosterone injection into the DH and VH via GRs activation impairs the reconsolidation of fear memory in a time-dependent manner.

Glucocorticoid- ß-adrenoceptors interactions in the infralimbic cortex in acquisition and consolidation of auditory fear memory extinction in rats.

This study investigated the interactive effect of glucocorticoid and ß-adrenoceptors in the infralimbic (IL) cortex on the acquisition and consolidation of fear extinction in rats' auditory fear conditioning (AFC) task. On day 1, rats underwent habituation for 9 min (12 tones, 10 s, 4 kHz, 80 dB, without footshock). On day 2 (conditioning), rats received 3 mild electrical footshocks (US; 2 s, 0.5 mA) paired with the auditory-conditioned stimulus (CS; tone: 30 s, 4 kHz, 80 dB). On days 3-5 (Ext 1-3), rats received 15 tones with no footshock in the test box. Intra-IL injection of corticosterone (CORT, 20 ng/0.5 µl per side) before Ext 1 and after Ext 1-2, respectively, facilitated the acquisition and consolidation of fear memory extinction. Intra-IL injection of the ß2-adrenoceptor agonist clenbuterol (CLEN, 50 ng/0.5 µl per side) inhibited, but the ß-adrenoceptor antagonist propranolol (PROP, 500 ng/0.5 µl per side) enhanced the facilitatory effects of CORT on fear memory extinction. CORT injection before the acquisition of fear extinction increased p-ERK levels in the IL. Co-injection of CORT with CLEN increased, but PROP decreased p-ERK activities. CORT injection after the consolidation of fear extinction increased p-CREB in the IL. Co-injection of CORT with CLEN increased, but PROP reduced p-CREB activities. Our findings show that corticosterone facilitates the acquisition and consolidation of fear memory extinction. GRs and ß-adrenoceptors in the IL jointly regulate fear memory extinction via ERK and CREB signaling pathways. This pre-clinical animal study may highlight the effect of GRs and ß-adrenoceptors of the IL cortex in regulating fear memory processes in fear-related disorders such as PTSD.

Corticosterone injection into the infralimbic prefrontal cortex enhances fear memory extinction: Involvement of GABA receptors and the extracellular signal-regulated kinase.

This study investigated the interactive effect of glucocorticoid and Gamma-aminobutyric acid (GABA) receptors in the Infralimbic (IL) cortex on fear extinction in rats' auditory fear conditioning task (AFC). Animals received 3 conditioning trial tones (conditioned stimulus, 30 s, 4 kHz, 80 dB) co-terminated with a footshock (unconditioned stimulus, 0.8 mA, 1 s). Extinction testing was conducted over 3 days (Ext 1-3) after conditioning. Intra-IL injection of corticosterone (CORT, 20 ng/0.3 µl/side) was performed 15 min before the first extinction trial (Ext 1) which attenuated auditory fear expression in subsequent extinction trials (Ext 1-3), demonstrating fear memory extinction enhancement. Co-injection of the GABAA agonist muscimol (250 ng/0.3 µl/side) or the GABAB agonist baclofen (250 ng/0.3 µl/side) 15 min before corticosterone, did not significantly affect the facilitative effects of corticosterone on fear extinction. However, co-injection of the GABAA antagonist bicuculline (BIC, 100 ng/0.3 µl/side) or the GABAB antagonist CGP35348 (CGP, 100 ng/0.3 µl/side) 15 min before corticosterone, blocked the facilitative effects of corticosterone on fear extinction. Moreover, extracellular signal-regulated kinase (ERK) and cAMP response element-binding (CREB) in the IL were examined by Western blotting analysis after the first extinction trial (Ext 1) in some groups. Intra-IL injection of corticosterone increased the ERK activity but not CREB. Co-injection of the bicuculline or CGP35348 blocked the enhancing effect of corticosterone on ERK expression in the IL. Glucocorticoid receptors (GRs) activation in the IL cortex by corticosterone increased ERK activity and facilitated fear extinction. GABAA or GABAB antagonists decreased ERK activity and inhibited corticosterone's effect. GRs and GABA receptors in the IL cortex jointly modulate the fear extinction processes via the ERK pathway. This pre-clinical animal study may highlight GRs and GABA interactions in the IL cortex modulating fear memory processes in fear-related disorders such as post-traumatic stress disorder (PTSD).

ß-adrenoceptors of the infra-limbic cortex mediate corticosterone-induced enhancement of acquisition and consolidation of fear memory extinction in rats.

The extinction of auditory fear conditioning (AFC) refers to reducing the fear responses induced following repeated presentation of a conditioned stimulus (tone) in the absence of an unconditioned stimulus (electric foot shock). Glucocorticoid receptors (GRs) play an important role in extinction, but the underlying neurobiological mechanisms are unclear. This study aimed to investigate the interaction between glucocorticoids and ß-adrenoceptors of the infra-limbic cortex (IL) in regulating the acquisition and consolidation of fear memory extinction in rats. Male rats were trained to AFC and received three trial tones (30 s, 4 kHz, 80 dB) co-terminated with a footshock (0.8 mA, 1 s; unconditioned stimulus). Extinction trials were conducted over 3 days after training (Ext 1-3). In experiment 1, rats received clenbuterol (0.25 mg/kg/2 ml, IP) as a ß2-adrenoceptor agonist or propranolol (2.5 mg/kg/2 ml, IP) as a ß-adrenoceptors antagonist before Ext 1 and immediately after Ext 1 and Ext 2 followed by systemic injection of corticosterone (3 mg/kg/2 ml, IP). In Experiment 2, separate groups of rats received a bilateral intra-IL injection of clenbuterol (50 ng/0.5 µl/side) or propranolol (500 ng/0.5 µl/side) followed by a systemic injection of corticosterone (3 mg/kg/2 ml) before Ext 1 and immediately after Ext 1 and Ext 2. Results indicated that systemic and intra-IL injections of clenbuterol and propranolol inhibited and increased the facilitative effects of corticosterone on fear memory extinction, respectively. These findings show that activating ß-adrenergic receptors in the IL mediates glucocorticoid effects on the acquisition and consolidation of auditory-conditioned fear memory extinction.