Figure 14.

Pharmacologic connectivity pathways implicated in neurosteroidal modulation of memory function. Neural networks that project to and/or share reciprocal connections with the hippocampus are modulated by neurosteroids as well as neurotransmitters. As a result, learning and memory deficits are associated with many of neurologic and neuropsychiatric disorders in which neurosteroids are implicated. The amygdala (shown in red), which is implicated in anxiety disorders, shares reciprocal connections with the hippocampus (shown in green). Progesterone, which is metabolized to ALLO, modulates emotional memory function by influencing amygdalar activity (64). The effects of neurosteroids on learning and memory for fear-inducing stimuli appears to be different in males and females which show different brain levels of ALLO at baseline as well (395). Neuroactive steroids, such as ALLO that enhance inhibitory neurotransmission can provide symptomatic relief from anxiety by reducing intra-network connectivity in the salience network and the amygdala (75, 192, 290, 291). ALLO induces an increase in functional connectivity between the amygdala and prefrontal cortex (shown in blue), which is involved in processing of complex social and non-social stimuli. However, the increased inhibition associated higher levels of ALLO can also interfere with episodic memory function which depends on intact functional connectivity between the hippocampus and the pre-cuneus (not shown) (203). Interestingly, both PREG, which is metabolized to ALLO, and PregS, which is a positive modulator of NMDARs, improve working memory function in patients with schizophrenia in which cortical disinhibition due to hypofunction of excitatory NMDARs on PV interneurons in the prefrontal cortex has been implicated (51, 52, 65, 237, 238). Parahippocampal and hippocampal structures including, the trisynaptic circuit receives sensory and emotional inputs from sensory modalities via the thalamus (shown in orange) and the amygdala, respectively (396–398). The impact of powerful emotion-evoking stimuli are state independent when ALLO is injected into the amygdala and hippocampus, but state-dependent when it is injected into the BNST (shown in gray) (246). The response of the hippocampal trisynaptic circuit to neurosteroids also depends on disease state-dependent changes in neurosteroid biosynthesis and receptor expression (399–401), as well as age-related changes in steroid hormone levels which converge to influence the responsivity of this circuit to endogenous and exogenous sources of neurosteroids and their synthetic analogs (229, 401–403).